Anthranilic acid derivatives as inhibitors of the CGMP-phosphodiesterase

ABSTRACT

Novel anthranilic acid derivatives having an inhibiting activity of cGMP-PDE are represented by the formula I where A is a lower alkylene group:  
                 
 
     The anthranilic acid derivatives show pharmacological activity and may be used in pharmaceutical compositions as medications. The anthranilic acid derivatives can be formed by the reaction of a fluoro precursor with an amine. Pharmaceutical compositions containing the anthranilic acid derivatives can be used to treat or prevent human health disorders.

TECHNICAL FIELD

[0001] This invention relates to novel anthranilic acid derivativeshaving pharmacological activity, to a process for their production, to apharmaceutical composition containing the same, and to their use as amedicament.

BACKGROUND ART

[0002] It is known that a cyclic guanosine-3′,5′-monophosphate(hereinafter referred to as cGMP) derived from aguanosine-5′-triphosphate possesses a relaxant activity of smooth muscleand that a cyclic guanosine-3′,5′-monophosphate phosphodiesterase(hereinafter refereed to as cGMP-PDE) acts to catalyze the degradationof cGMP to a guanosine-5′-monophosphate. The compounds having aninhibitory activity of cGMP-PDE are disclosed in European PatentPublication Nos. 579,496; 534,443; 526,004; 636,626; U.S. Pat. Nos.3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos.93/07,124; 94/19,351; 95/18,097; 96/32,379; Japan Patent PublicationNos. 05-222,000; 07-330,777; and so on.

DISCLOSURE OF INVENTION

[0003] This invention relates to novel anthranilic acid derivatives,which have pharmaceutical activity such as inhibiting activity ofcGMP-PDE, to a process for their production, to a pharmaceuticalcomposition containing the same and to a use thereof.

[0004] Accordingly, one object of this invention is to provide the novelanthranilic acid derivatives, which have an inhibiting activity ofcGMP-PDE.

[0005] Another object of this invention is to provide a process forproduction of the anthranilic acid derivatives.

[0006] A further object of this invention is to provide a pharmaceuticalcomposition containing, as an active ingredient, an anthranilic acidderivative.

[0007] Still further object of this invention is to provide a use of theanthranilic acid derivatives for treating or preventing variousdiseases.

[0008] The new anthranilic acid derivatives of this invention can berepresented by the following formula (I)

[0009] wherein

[0010] R¹ is hydrogen atom or a halogen atom;

[0011] R² is an electron withdrawing group;

[0012] R³ is hydrogen atom; hydroxy group; a lower alkoxy group; acycloalkyl group; a substituted or unsubstituted aryl group; or anunsaturated heterocyclic group optionally substituted with lower alky;

[0013] A is a lower alkylene group;

[0014] R⁴ is a lower alkoxy group,

[0015] a substituted or unsubstituted, saturated or unsaturatedheterocyclic group,

[0016] an amino group optionally substituted with halo(lower)alkyl orlower alky,

[0017] a group —CH₂—R⁵

[0018] wherein R⁵ is a cycloalkyl group or an unsaturated heterocyclicgroup, or

[0019] a group —CR⁶R⁷R⁸ wherein

[0020] R⁶ and R⁷ are each independently carboxy group,

[0021] a protected carboxy group,

[0022] a carbamoyl group optionally substituted with lower alkyl, or

[0023] a lower alkyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen atom; hydroxygroup; cyano group; azido group; lower alkoxy group; lower alkylthiogroup;

[0024] protected carboxy group; lower alkanesulfonyl group; acyloxygroup; lower alkanesulfonyloxy group; aryl group; aryloxy group whichmay be substituted with cyano; unsaturated heterocyclic group which maybe substituted with lower alkyl; guanidino group which may besubstituted with lower alkyl, cyano and/or halogen; isothioureido groupwhich may be substituted with lower alkyl and/or cyano; and amino groupwhich may be substituted with acyl, protected carboxy, loweralkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or

[0025] R⁶ and R⁷ together with the carbon atom to which R⁶ and R⁷ areattached may form a substituted or unsubstituted, saturated carbocyclicgroup, or an unsaturated carbocyclic group optionally substituted withhydroxy, and

[0026] R⁸ is hydrogen atom; a lower alkoxy group; or a lower alkyl groupoptionally substituted with hydroxy or lower alkoxy;

[0027] provided that

[0028] when R⁴ is the group —CR⁶R⁷R⁸ wherein

[0029] R⁶ is a lower alkyl group optionally substituted with halogen,

[0030] R⁷ is a lower alkyl group optionally substituted with halogen,

[0031] and R⁸ is hydrogen atom or a lower alkyl group, or

[0032] when R⁴ is the group —CH₂—R⁵ wherein R⁵ is the same as the above,R³ should be hydrogen atom, hydroxy group or a cycloalkyl group; and apro-drug thereof, and a salt thereof.

[0033] The compounds of the formula (I) may contain one or moreasymmetric centers and thus they can exist as enantiomers ordiastereoisomers.

[0034] The compounds of the formula (I) may also exist in tautomericforms and the invention includes both mixtures and separate individualtautomers.

[0035] It is further to be noted that isomerization or rearrangement ofthe compounds (I) may occur by the effect of light, acid, base or thelike, and the compounds obtained as the result of said isomerization orrearrangement are also included within the scope of the presentinvention.

[0036] The compounds of the formula (I) and its salts can be in the formof a solvate, which is included within the scope of the presentinvention.

[0037] The solvate preferably include a hydrate and an ethanolate.

[0038] Also included in the scope of invention are radiolabelledderivatives of compounds of formula (I) which are suitable forbiological studies.

[0039] According to this invention, the object compounds (I) or itssalts can be prepared by the following process.

[0040] Process 1

[0041] Process 2

[0042] Process 3

[0043] In the above formulae, R¹, R², R³, R⁴, R⁶, R⁷ and A are the sameas those defined in the above.

[0044] Some of the starting materials are novel and can be prepared bythe following processes.

[0045] Process A

[0046] Process B

[0047] Process C

[0048] Process D

[0049] In the above formulae, R¹, R², R³, R⁴, R⁶, R⁷and A are the sameas those defined in the above, R is hydrogen atom or a lower alkylgroup.

[0050] In the above and subsequent descriptions of the presentspecification, suitable examples and illustrations of the variousdefinitions which the present invention includes within the scope areexplained in detail in the following.

[0051] The term “lower” is intended to mean a group having 1 to 6 carbonatom(s), unless otherwise indicated.

[0052] Suitably the lower alkyl groups and lower alkyl moieties in theterms of the halo(lower)alkyl, lower alkanesulfonyl, loweralkanesulfonyloxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl,ar(lower) alkyl, ar(lower)alkoxy and ar(lower)alkoxycarbonyl groups mayinclude straight or branched ones having 1 to 6 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl or the like, more suitably the oneshaving 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl or isobutyl.

[0053] Suitably the examples of the lower alkenyl groups includestraight or branched ones having 2 to 6 carbon atoms, such as ethenyl,propenyl (i.e., alkyl or 1-propenyl), butenyl, isobutenyl, pentenyl,hexenyl or the like.

[0054] Suitable lower alkylene groups and lower alkylene moieties in thelower alkylenedioxy group may include straight or branched ones having 1to 6 carbon atoms, such as methylene, methylmethylene, ethylene,methylethylene, trimethylene, tetramethylene, 2-methyltrimethylene,pentamethylene, hexamethylene or the like, more suitably the ones having1 to 3 carbon atoms.

[0055] Suitable examples of the acyl groups and acyl moieties in theterm of the acyloxy group include aliphatic acyl groups such as loweralkanoyls (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, oxalyl, succinyl or pivaloyl) and acyl groupscontaining an aromatic or heterocyclic ring such as aroyls (e.g.,benzoyl, toluoyl, xyloyl or naphthoyl), ar(lower)alkanoyls (e.g.,phenylacetyl or phenylpropionyl), ar(lower)alkoxycarbonyls (e.g.,benzyloxycarbonyl or phenethyloxycarbonyl), heterocyclic carbonyls(e.g., thenoyl or furoyl) and the like.

[0056] The cycloalkyl groups may include the ones having 3 to 7 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or the like.

[0057] Suitably the aryl groups and aryl moieties in the terms of thear(lower)alkyl, ar(lower)alkoxy, aryloxy, aryloxycarbonyl and aroyloxygroups may be an aromatic group having 6 to 12 carbon atoms. Specificexamples thereof are phenyl, naphthyl, indenyl, azulenyl, biphenylenyl,fluorenyl and anthracenyl.

[0058] Suitable examples of the saturated carbocyclic groups may be thecycloalkyl groups as exemplified in the above.

[0059] Suitable examples of unsaturated carbocyclic groups may includecyclopentenyl, cyclohexenyl, cycloheptenyl, 2,3-dihydro-1H-indenyl,benzocyclohexyl and the like.

[0060] Suitable examples of the halogen atoms and halo moiety of thehalo(lower)alkyl group may be fluorine, chlorine, bromine or iodine.

[0061] Suitable examples of the unsaturated heterocyclic group mayinclude mono- or poly-cyclic groups containing at least one hetero atomselected from nitrogen, sulfur and oxygen atoms, such as

[0062] (1) unsaturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl] tetrazolyl [e.g., 1H-tetrazolyor 2H-tetrazolyll or the like.;

[0063] (2) unsaturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing an oxygen atom, for example, pyranylor furyl;

[0064] (3) unsaturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms, for example,thienyl or the like;

[0065] (4) unsaturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like;

[0066] (5) unsaturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or thelike;

[0067] (6) unsaturated condensed heterocyclic groups containing 1 to 2nitrogen atoms, for example, indolyl, indazolyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl, benzimidazolyl or the like;

[0068] (7) unsaturated condensed heterocyclic groups containing 1 to 2oxygen atoms, for example, benzofuryl or the like;

[0069] (8) unsaturated condensed heterocyclic groups containing 1 to 2sulfur atoms, for example, benzo[b]thienyl or the like;

[0070] (9) unsaturated condensed heterocyclic groups containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl,benzoxadiazolyl, phenoxazinyl or the like;

[0071] (10) unsaturated condensed heterocyclic groups containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl,benzoisothiazolyl, phenothiazinyl or the like.

[0072] Suitable examples of the saturated heterocyclic group andheterocyclic moiety in the saturated heterocyclic sulfonyl group includemonocyclic groups containing at least one hetero atom selected fromnitrogen, sulfur and oxygen atoms, such as

[0073] (1) saturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.,pyrrolidinyl, imidazolidinyl, piperidyl or piperazinyl];

[0074] (2) saturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g., morpholinyl];

[0075] (3) saturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl or thiomorpholinyl];

[0076] (4) saturated 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms and/or 1 to 2oxygen atoms [e.g., tetrahydrothiophenyl, tetrahydrothiopyranyl,1-oxotetrahydrothiopyranyl, 1, 1-dioxotetrahydrothiopyranyl,dioxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dioxanyl); orthe like.

[0077] Suitably carboxy protective groups in the protected carboxy groupmay include lower alkyl groups (e.g., methyl, ethyl or tert-butyl),halo(lower)alkyl groups (e.g., 2-iodomethyl or 2,2,2-trichloroethyl),ar(lower)alkyl groups (e.g., benzyl, trityl, 4-methoxybenzyl,4-nitrobenzyl, 25 phenethyl, bis(methoxyphenyl)methyl,3,4-dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl), aryl groups(e.g., phenyl, naphthyl, tolyl or xylyl), and the like, more suitablythe lower alkyl groups such as methyl, ethyl or tert-butyl andar(lower)alkyl groups such as benzyl.

[0078] Specific examples of the each group containing theabove-mentioned moiety and having substituent(s) are as follows.

[0079] As the halo(lower) alkyl group, fluoromethyl, iodomethyl,chloromethyl, trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl or the like may be mentioned.

[0080] The lower alkanesulfonyl group is methanesulfonyl(mesyl),ethanesulfonyl, propanesulfonyl or the like.

[0081] The lower alkanesulfonyloxy group is methan sulfonyloxy(mesyloxy), ethanesulfonyloxy, propanesulfonyloxy or the like.

[0082] The lower alkoxy group is methoxy, ethoxy, propoxy, n-butoxy,tert-butoxy of the like.

[0083] The lower alkylthio group is methylthio, ethylthio, propylthio,butylthio, isobutylthio or the like.

[0084] The acyloxy group is formyloxy, acetyloxy, propionyloxy,benzoyloxy, toluoyloxy, naphthoyloxy, phenylacetyloxy, theonyloxys orthe like.

[0085] The hydroxy(lower)alkyl group is hydroxymethyl, hydroxyethyl orthe like.

[0086] The ar(lower)alkyl group is benzyl, 4-methoxybenzyl,4-nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl,3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl) or the like.

[0087] The ar(lower)alkoxy group is benzyloxy, 4-methoxybenzyloxW,4-nitrobenzyloxy, phenethyloxy, trityloxy, bis(methoxyphenyl)methoxy,3,4-dimethoxybenzyloxy, 4-hydroxy-3,5-di-tert-butylbenzyloxy or thelike.

[0088] The lower alkylenedioxy group is methylenedioxy, ethylenedioxyand the like.

[0089] The aryloxy group is phenoxy, naphthoxy, tolyloxy, xylyloxy orthe like.

[0090] The aroyloxy group is benzoyloxy, naphthoyloxy or the like.

[0091] The saturated heterocyclic sulfonyl group is piperazinesulfonyl,piperizinesulfonyl, morpholinesulfonyl, pyrazolidinesulfonyl or thelike.

[0092] Preferred embodiments of the compounds (I) are those representedby the formula (I),

[0093] wherein

[0094] R¹ is hydrogen atom or a halogen atom;

[0095] R² is an electron withdrawing group;

[0096] R³ is hydrogen atom; hydroxy group; a lower alkoxy group; acycloalkyl group; a substituted or unsubstituted aryl group; or anunsaturated heterocyclic group optionally substituted with lower alkyl;

[0097] A is a lower alkylene group;

[0098] R⁴ is a lower alkoxy group,

[0099] a substituted or unsubstituted, saturated or unsaturatedheterocyclic group,

[0100] an amino group optionally substituted with halo(lower)alkyl orlower alkyl,

[0101] a group —CH₂—R⁵ wherein R⁵ is a cycloalkyl group or anunsaturated heterocyclic group, or

[0102] a group —CR⁶R⁷R⁸ wherein

[0103] R⁶ and R⁷ are each independently

[0104] carboxy group,

[0105] a protected carboxy group,

[0106] a carbamoyl group optionally substituted with lower alkyl, or

[0107] a lower alkyl group optionally substituted with one or moresubstituents selected from the group consisting of halogen atom; hydroxygroup; cyano group; azido group; lower alkoxy group; lower alkylthiogroup; protected carboxy group; lower alkanesulfonyl group; acyloxygroup; lower alkanesulfonyloxy group; aryl group; aryloxy group whichmay be substituted with cyano; unsaturated heterocyclic group which maybe substituted with lower alkyl; guanidino group which may besubstituted with lower alkyl, cyano and/or halogen; isothioureido groupwhich may be substituted with lower alkyl and/or cyano; and amino groupwhich may be substituted with acyl, protected carboxy, loweralkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or

[0108] R⁶ and R⁷ together with the carbon atom to which R⁶ and R⁷ areattached may form a substituted or unsubstituted, saturated carbocyclicgroup, or

[0109] an unsaturated carbocyclic group optionally substituted withhydroxy, and

[0110] R⁸ is hydrogen atom; a lower alkoxy group; or a lower alkyl groupoptionally substituted with hydroxy or a lower alkoxy;

[0111] provided that

[0112] when R⁴ is the group —CR⁶R⁷R⁸ wherein

[0113] R⁶ is a lower alkyl group optionally substituted with halogen,

[0114] R⁷ is a lower alkyl group optionally substituted with halogen,

[0115] and R⁸ is hydrogen atom or a lower alkyl group, or

[0116] when R⁴ is the group —CH₂—R⁵ wherein R⁵ is the same as the above,Rshould be hydrogen atom, hydroxy group or a cycloalkyl group, theelectron withdrawing group for Rbeing selected from a group consistingof nitro group; cyano group; acyl group; halo(lower)alkyl group;sulfamoyl group; carbamoyl group optionally substituted with loweralkyl; halogen atom; lower alkenyl group optionally substituted withprotected carboxy; lower alkanesulfonyl group; saturated heterocyclicsulfonyl group optionally substituted with protected carboxy; andunsaturated heterocyclic group,

[0117] the substituent(s) on the aryl group for R³ being selected from agroup consisting of lower alkyl group; halo(lower)alkyl group; loweralkylthio group; halogen atom; hydroxy group; lower alkylenedioxy group;cyano group; nitro group; carboxy group; protected carboxy group;sulfamoyl group; acyl group; aryl group; ar(lower)alkoxy group; aryloxygroup; lower alkoxy group which may be substituted with lower alkoxy orcycloalkyl; amino group which may be substituted with acyl, protectedcarboxy or lower alkyl; and carbamoyl group which may be substitutedwith lower alkyl,

[0118] the substituent(s) on the saturated or unsaturated heterocyclicgroup for R⁴ being selected from a group consisting of oxo group; acylgroup; protected carboxy group; lower alkanesulfonyl group; sulfamoylgroup which may be substituted with protected carboxy; ar(lower)alkylgroup; lower alkyl group which may be substituted with hydroxy or aryl;ureido group which may be substituted with lower alkyl; guanidino groupwhich may be substituted with protected carboxy; amidino group which maybe substituted with protected carboxyl; and carbamoyl group which may besubstituted with lower alkyl, and

[0119] the substituent(s) on the saturated carbocyclic group formed bycombination of R⁶ and R⁷ being selected from a group consisting of loweralkyl group; halogen atom; hydroxy group; lower alkoxy group; acyloxygroup; carboxy group; protected carboxy group; oxo group; amidino groupwhich may be substituted with protected carboxy; ureido group which maybe substituted with lower alkyl or aryl; guanidino group which may besubstituted with protected carboxy; amino group which may be substitutedwith acyl, lower alkanesulfonyl or protected carboxy; and carbamoylgroup which may be substituted with lower alkyl or hydroxy(lower)alkyl;

[0120] and a pro-drug thereof, and a salt thereof.

[0121] Another preferred embodiments are as follows:

[0122] compounds of the formula (I),

[0123] wherein

[0124] R¹ is hydrogen atom or a halogen atom;

[0125] R² is an electron withdrawing group;

[0126] R³ is a substituted or unsubstituted aryl group;

[0127] A is a lower alkylene group; and

[0128] R⁴ is a group —CR⁶R⁷R⁸ wherein

[0129] R⁶ and R⁷ together with the carbon atom to which R⁶ and R⁷ areattached may form a substituted or unsubstituted, saturated carbocyclicgroup, and

[0130] R⁸ is hydrogen atom; and

[0131] compounds of the formula (I), wherein

[0132] R¹ is hydrogen atom or a halogen atom;

[0133] R² is an electron withdrawing group;

[0134] R³ is a substituted or unsubstituted aryl group;

[0135] A is a lower alkylene group; and

[0136] R⁴ is a group —CR⁶R⁷R⁸ wherein

[0137] R⁶ is a lower alkyl group substituted with hydroxy,

[0138] R⁷ is a lower alkyl which may be substituted with hydroxy, and

[0139] R⁸ is hydrogen atom or a lower alkyl group which may besubstituted with hydroxy.

[0140] Further preferred embodiments are as follows:

[0141] compounds of the formula (I), wherein

[0142] R¹ is hydrogen atom or a halogen atom;

[0143] R² is nitro group, cyano group or a halo(lower)alkyl group;

[0144] R³ is an aryl group optionally substituted with one or moresubstituent(s) selected from halogen and lower alkoxy;

[0145] A is a lower alkylene group; and

[0146] R⁴ is a group —CR⁶R⁷R⁸ wherein

[0147] R⁶ and R⁷ together with the carbon atom to which R⁶ and R⁷ areattached may form a saturated carbocyclic group optionally substitutedwith hydroxy or amino which may be substituted with acyl; and

[0148] R⁸ is hydrogen atom; and

[0149] compounds of the formula (I), wherein

[0150] R¹ is hydrogen atom or a halogen atom;

[0151] R² is nitro group, cyano group or a halo(lower)alkyl group;

[0152] R³ is an aryl group optionally substituted with one or moresubstituent(s) selected from halogen and lower alkoxy;

[0153] A is a lower alkylene group; and

[0154] R⁴ is a group —CR⁶R⁷R⁸ wherein

[0155] R⁶ is a lower alkyl group substituted with hydroxy,

[0156] R⁷ is a lower alkyl group which may be substituted with hydroxy,and

[0157] R⁸ is hydrogen atom or a lower alkyl group which may besubstituted with hydroxy.

[0158] In accordance with the invention, it includes salts of thecompounds (I). The salts may be conventional non-toxic pharmaceuticallyacceptable salts, for example, a salt with an alkali metal (e.g., sodiumor potassium) and an alkaline earth metal (e.g., calcium or magnesium),an ammonium, an organic base (e.g., trimethylamine, triethylamine,pyridine, picoline, dicyclohexylamine or dibenzylethylenediamine), anorganic acid (e.g., acetic acid, benzoic acid, succinic acid, fumaricacid, maleic acid, lactic acid, citric acid, tartaric acid, gluconicacid, methanesulfonic acid, benzenesulfonic acid, formic acid,p-toluenesulfonic acid or trifluoroacetic acid), inorganic acid (e.g.,hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid),an amino acid (e.g., arginine, aspartic acid or glutarnic acid) or thelike.

[0159] The processes for preparing the starting compounds and the objectcompounds (I) of the present invention are explained in detail in thefollowing.

[0160] Process 1

[0161] A compound (I) or its salt can be prepared by reacting a compound(II) or its salt with a compound (III) or its salt.

[0162] This reaction is usually carried out in the presence of aninorganic or an organic base.

[0163] Suitable inorganic base may include an alkali metal [e.g., sodiumor potassium], an alkali metal hydroxide [e.g., sodium hydroxide orpotassium hydroxide], an alkali metal hydrogen carbonate [e.g., sodiumhydrogen carbonate or potassium hydrogen carbonate], an alkali metalcarbonate [e.g., sodium carbonate], an alkali earth metal carbonate[e.g., calcium carbonate], an alkali metal hydride [e.g., sodium hydrideor potassium hydridel and the like.

[0164] Suitable organic base may include tri(lower)alkylamines [e.g.,triethylamine or N,N-diisopropylethylamine], alkyl lithiums [e.g.,methyl lithium or butyl lithium], lithium diisopropylamide, lithiumhexamethyldisilazido and the like.

[0165] The reaction is usually carried out in a conventional solventsuch as water, alcohols [e.g., methanol, ethanol or isopropyl alcohol],tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,N,N-dimethylformamide or any other organic solvent which does notadversely affect the reaction, or a mixture thereof.

[0166] The reaction is preferably carried out at a temperature undercooling to warming. However, the reaction temperature is not limited.

[0167] Process 2

[0168] A compound (I) or its salt can be prepared by reacting a compound(IV) or its reactive derivative at the carboxy group, or its salt, witha compound (V) or its reactive derivative at the amino group, or itssalt, according to a procedure known in the art.

[0169] Suitable reactive derivatives at the carboxy group of thecompound (IV) may include the acid chloride, azide, acid anhydride,activated amide, activated ester and the like.

[0170] Suitably the acid anhydride may include anhydrides with an acidsuch as substituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acidor halogenated phosphoric acid), dialkylphosphorous acid, sulfuric acid,thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid orethanesulfonic acid), alkanoic acid (e.g., pivalic acid, pentanoic acidor isopentanoic acid), aromatic carboxylic acid (e.g., benzoic acid,chlorobenzoic acid, fluorobenzoic acid or nitrobenzoic acid),or thelike.

[0171] Suitably the active amide may include the imidazoylylamide,4-substituted imidazoylylamide, dimethylpyrazolylamide, triazolylamidetetrazolylamide or the like.

[0172] Suitably the active ester may include the dimethyliniinomethyl[(CH₃)₂N³⁰=CH⁻]ester, vinyl ester, propargyl ester, 4-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester,p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, 8-quinolyl thioester, an ester with a N-hydroxy compound (e.g.,N,N-dimethylhydroxylamine, 1-hydroxy-2H-pyridone, N-hydroxysuccinimide,N-hydroxybenzotriazole or N-hydroxyphthalimide) or the like.

[0173] Suitably the reactive derivative at amino group of the compound(V) may include Schiffs base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (V) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (V) with a silylating reagent such astrimethylsilylchloride, N,O-bis(trimethylsilyl)acetamide,N-trimethylsilylacetamide or the like.

[0174] Each reactive derivative of compounds (IV) and (V) can optionallybe selected from the above according to the kinds of the compounds (IV)and (V) to be used, respectively.

[0175] When the compound (IV) is used in a free acid form or its saltform in the reaction, the reaction is preferably carried out in thepresence of a condensing agent.

[0176] Suitable condensing agent may include carbodiimides (e.g.,N,N-dicyclohexylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodimide orN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide or its hydrochloride),diphenylphosphinic azide, diphenylphosphinic chloride, diethylphosphoryl cyamide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride,N,N′-carbonyldiimidazole,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, cyanuric chloride or thelike.

[0177] The reaction may be also carried out in the presence of anorganic or inorganic base such as an alkali metal carbonate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine or the like.

[0178] The reaction is usually carried out in a conventional solventsuch as water, acetone, alcohols [e.g., methanol, ethanol or isopropylalcohol], tetrahydrofuran, dioxane, toluene, methylene chloride,chloroform, N,N′-dimethylformamide or any other organic solvent whichdoes not adversely affect the reaction, or a mixture thereof.

[0179] The reaction is preferably carried out at a temperature undercooling to warming. However, the reaction temperature is not limited.

[0180] Process 3

[0181] A compound (I-1) or its salt can be prepared by reacting acompound (VI) or its salt with a ketone compound(VII) in the presence ofan inorganic acid (e.g., sulfuric acid or hydrogen chloride) or anorganic acid (e.g., acetic acid) and a reducing agent.

[0182] Suitable reducing agent may include sodium cyanoborohydride,sodium triacetoxyborohydride, sodium borohydride, borane-pyridinecomplex and the like.

[0183] The reaction is usually carried out in a conventional solventsuch as alcohols (e.g., methanol or ethanol), tetrahydrofuran, dioxane,toluene or any other organic solvent which does not adversely affect thereaction, or a mixture thereof.

[0184] The reaction is preferably carried out at a temperature undercooling to ambient temperature. However, the reaction temperature is notlimited.

[0185] Instead of the ketone compound(VII), its corresponding aldehydemay be used in this reaction.

[0186] Process A

[0187] The process A can be carried out in a manner similar to Process 2by using a 2-fluorobenzoic acid derivative (VIII) and an amine compound(V) to obtain the compound (II).

[0188] Process B

[0189] The process B can be carried out in a manner similar to Process 3by using an aminobenzoate derivative (IX) and a ketone compound (VII) toobtain the compound (IV-1).

[0190] Process C

[0191] The process C can be carried out in a manner similar to Process 1by using a 5-fluorobenzoate derivative (X) and an amine compound (III)to obtain the compound (IV).

[0192] Process D

[0193] The compound (VI) can be prepared by reacting an isatoicanhydride derivative (XI) with an amine compound (V).

[0194] This reaction is usually carried out in a conventional solventsuch as acetone, tetrahydrofuran, dioxane, toluene, methylene chloride,chloroform, N,N′-dimethylformamide or any other organic solvent whichdoes not adversely affect the reaction, or a mixture thereof.

[0195] The reaction is preferably carried out at a temperature undercooling to amibient temperature. However, the reaction temperature isnot limited.

[0196] A pharmaceutically acceptable salt of the compound (I) can beprepared by treating a compound (I) with an appropriate base or acid inaccordance with the conventional method.

[0197] The compounds (I) and pharmaceutically acceptable salts thereofpossess inhibitory activity of cGMP-PDE (especially PDE-V), relaxantactivity of smooth muscle, bronchodilator activity, vasodilativeactivity, relaxant activity of the penile corpus cavernosum, inhibitoryactivity of smooth muscle cells proliferation, inhibitory activity ofallergy, and so on.

[0198] The compounds (I) and pharmaceutically acceptable salts thereof,therefore, are useful for the treatment and/or prevention of variousdiseases, such as angina, hypertension, pulmonary hypertension,congestive heart failure, glomerular diseases (e.g., diabeticglomerulosclerosis), renal tubulo-intestitinal diseases (e.g.,nephropathy induced by tacrolimus, cyclosporin or the like), renalfailure, atherosclerosis, conditions of reduced blood vessel patency(e.g., post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, stroke, chronic reversible obstructive lung diseases(e.g., bronchitis or asthma (chronic asthma, allergic asthma)), allergicrhinitis, urticaria, glaucoma, diseases characterized by disorders ofgut motility (e.g., irritable bowel syndrome), electile dysfunction(e.g., organic electile dysfunction or psychic electile dysfunction),female sexual dysfunction, impotence, or diabetic complications (e.g.,diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis,diabetic dermopathy, diabetic neuropathy, diabetic cataract or diabeticretinopathy).

[0199] Further, the compounds (I) and pharmaceutically acceptable saltsthereof are also useful for the treatment and/or prevention ofmicturition disorder, incontinence or storage of urine disorder (such asthe ones ascribed to nerve regressive affection, inflammation, injury,neoplasm, diabetes mellitus, cerebral vascular accident, surgery,prostatomegaly, urethra relaxation incompetence, dysuria).

[0200] It is to be noted that improvement of sexual performance is alsoincluded in the treatment of electile dysfunction or impotence.

[0201] The compounds (I) and their salts of the present invention havemuch advantages, such as stronger activity, more suitable half-life,decreased adverse effect, or the like, compared to the known anthranilicacid derivatives having an inhibitory activity of cGMP-PDE, which areshown in the prior arts.

[0202] In order to exhibit the usefulness of the present invention, theactivities of the compounds (I) are shown in the following.

[0203] [I] Test Compound:

[0204] The test compounds are shown in Tables 1 and 2 and test methods 2and 3.

[0205] [II] Test Method 1: cGMP-Phosphodiesterase (PDE) Assay

[0206] Human platelet cGMP-PDE was separated from other isozymes inhuman platelets by a modification of the method of Thompson et. al. (seeCyclic Nucleotide Phosphodiesterase (PDE), in Methods of Enzymaticanalysis, Vol 4, pl27-234, 1984). In enzyme inhibition assays, the testcompounds were dissolved in DMSO and then diluted with assay buffer (50mM Tris-HCl, 0.077 mg/ml dithiothreitol and 10 mg/ml snake venom, 1 mMEGTA, pH 8.0), at final concentrations ranging from 10⁻¹⁰ to 10⁻⁶ M.Assays were performed at 0.1 μM substrate ([³H]-cGMP) concentration, at30° C. for 10 minutes using enzymne dilutions which gave 10-20%hydrolysis of substrate. Each assay was initiated by addition ofsubstrate and terminated by addition of anion exchange resin (Dowex®1-X8, 250 mg/mg) followed by centrifugation for 10 minutes (3000 rpm, at4° C.). Radioactivity of supernatant (³H-GMP) was assayed by liquidscintillation counting.

[0207] The obtained results in enzymatic inhibitory test against humanplatelet PDE-V are shown in Table 1. TABLE 1 Inhibitory activity TestCompounds (nM) IC₅₀(nM) 2-(cyclopentylamino)-N-hexyl-5-nitrobenzamide<10 N-(2-chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide <10N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide <10N-(4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide <102-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5- <10 nitrobenzamide2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5- <10 nitrobenzamide2-(cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide <102-(cyclopentylamino)-N-(4-methylbenzyl)-5-nitrobenzamide <102-(cyclopentylamino)-N-(4-methoxybenzyl)-5- <10 nitrobenzamide2-(cyclopentylamino)-5-nitro-N-[4-(trifluoromethyl)benzyl]- <10benzamide N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide <10N-(4-amino-2-chlorobenzyl)-2-(cyclopentylamino)-5- <10 nitrobenzamideN-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5- <10 nitrobenzamide2-(cyclopentylamino)-5-nitro-N-(4-nitrobenzyl)benzamide <10N-(4-bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide <102-(cyclopentylamino)-N-furfuryl-5-nitrobenzamide <102-(cyclopentylamino)-5-nitro-N-(2-thienyl-methyl)-benzamide <102-(cyclopentylamino)-N-(4-hydroxy-3-methoxybenzyl)-5- <10 nitrobenzamide2-(cyclopentylamino)-5-nitro-N-phenethylbenzamide <102-(cyclopentylamino)-5-nitro-N-(3-phenyl-propyl)benzamide <10N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide <10N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide <102-(cyclopentylamino)-N-(2,4-difluorobenzyl)-5- <10 nitrobenzamideN-[(2-benzimidazolyl)methyl]-2-(cyclopentylamino)-5- <10 nitrobenzamideN-benzyl-2-(cyclopropylamino)-5-nitrobenzamide <10N-benzyl-2-(trans-2-hydroxycyclopentylamino)-5- <10 nitrobenzamide5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H- <10thiopyran-4-ylamino)benzamide2-(tert-butylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)- <10benzamide 2-[1-(ethoxycarbonyl)piperidin-4-ylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide2-(1-benzylpiperidin-4-ylamino)-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide(R)-2-(1-ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide(R)-5-Nitro-2-(tetrahydro-3-furanylamino)-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide2-(1,1-dioxotetrahydro-2H-thiopyran-4-ylamino)-5-nitro-N- <10(1,3-benzodioxol-5-ylmethyl)-benzamide2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol- <105-ylmethyl)benzamide 2-(4-carbamoylcyclohexylamino)-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide(R)-2-[1-(methoxycarbonyl)ethylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamideN-benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide <102-[3-(benzoyloxy)cyclopentylamino]-N-benzyl-5- <10 nitrobenzamide2-[1-(hydroxymethyl)cyclopentylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide(S)-2-[1-(hydroxymethyl)-2-methylpropylamino]-5-nitro-N- <10(1,3-benzodioxol-5-ylmethyl)-benzamide5-nitro-2-(4-oxocyclohexylamino)-N-(1,3-benzodioxol-5- <10ylmethyl)benzamide2-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl-amino]-5- <10nitro-N-(1,3-benzodioxol-5-yl-methyl)benzamide2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-nitro-N- <10(1,3-benzodioxol-5-ylmethyl)-benzamide5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5- <10ylmethyl)benzamide 2-[1-(hydroxyethyl)pentylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide2-(1-acetyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol- <105-ylmethyl)benzamide 2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide2-(1-formyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol- <105-ylmethyl)benzamide N-(3-fluoro-4-methoxybenzyl)-2-[2-hydroxy-1- <10(hydroxymethyl)ethylamino]-5-nitrobenzamide2-(trans-4-hydroxycyclohexyl)amino-N-[4- <10(methylthio)benzyl]-5-nitrobenzamideN-(3,5-dichloro-4-methoxybenzyl)-2-(trans-4- <10hydroxycyclohexylamino)-5-nitrobenzamideN-(3,4-ethylenedioxybenzyl)-2-(trans-4- <10hydroxycyclohexylamino)-5-nitrobenzamideN-(3-chloro-4-fluorobenzyl)-2-[2-hydroxy-1- <10(hydroxymethyl)ethylamino]-5-nitrobenzamide(S)-N-(3-chloro-4-methylbenzyl)-2-(2-hydroxy-1- <10methylethylamino)-5-nitrobenzamide2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-N-(3-methoxy- <104-methylbenzyl)-5-nitrobenzamideN-cyclohexylmethyl-2-(cis-4-hydroxycyclohexylamino)-5- <10nitrobenzamide (S)-2-[1-(chloromethyl)propylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide(R)-N-(4-chloro-3-nitrobenzyl)-2-[1-(hydroxy- <10methyl)propylamino]-5-nitrobenzamideN-(3,4-dimethylbenzyl)-2-(cis-4-hydroxycyclohexylamino)-5- <10nitrobenzamide2-(cis-4-chlorocyclohexylamino)-5-nitro-N-(1,3-benzodioxol- <105-ylmethyl)benzamide 2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4- <10dimethoxybenzyl)-5-nitrobenzamide2-[(trans-4-aminocyclohexyl)amino]-N-(3,4- <10dimethoxybenzyl)-5-nitrobenzamide2-[2-chloro-1-(chloromethyl)ethylamino]-5-nitro-N-(1,3- <10benzodioxol-5-ylmethyl)benzamide N-(2-chloro-5-methoxybenzyl)-2-(cis-4-<10 hydroxycyclohexylamino)-5-nitrobenzamideN-(3-chloro-4-methoxybenzyl)-2-[2-hydroxy-1- <10(hydroxymethyl)ethylaminol]-5-(trifluoromethyl)-benzamideN-(3,4-dimethoxylbenzyl)-2-[(1R,2S)-2-hydroxy-1-methyl- <102-phenylethyl]amino-5-nitrobenzamideN-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5- <10ylamino)-5-nitrobenzamide N-(3,4-dimethoxybenzyl)-5-nitro-2-[trans-4-(3-<10 propylureido)cyclohexylamino]benzamideN-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5- <10ylamino)benzamide N-(4-chloro-4-ethoxybenzyl)-2-(cis-4- <10hydroxycyclohexylamino)-5-nitrobenzamideN-(4-ethoxy-3-methoxybenzyl)-2-(cis-4- <10hydroxycyclohexylamino)-5-nitrobenzamide2-{trans-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]cyclo- <10hexylamino}-N-(3 ,4-dimethoxybenzyl)-5-nitrobenzamide2-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]-N-(3,4- <10dimethoxybenzyl)-5-nitrobenzamide(R)-2-(2-hydroxy-1-methylethyl)amino-5-nitro-N-(4- <10phenoxybenzyl)benzamide N-(4-ethoxy-3-methoxybenzyl)-2-(trans-4- <10formamidocyclohexylamino)-5-nitrobenzamideN-(3,4-dimethoxybenzyl)-5-nitro-2-(4-piperidinyl- <10 amino)benzamideN-(3,4-dimethoxybenzyl)-2-(trans-4-guanidino- <10cyclohexylamino)-5-nitrobenzamide hydrochloride(R)-2-(2-hydroxy-1-methylethyl)amino-5-nitro-N-(4- <10phenybenzyl)benzamide N-(benzo[b]thiophen-2-ylmethyl)-2-(cis-4- <10hydroxycyclohexylamino)-5-nitrobenzamide2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(4- <10phenylbenzyl)benzamideN-(3,4-dimethoxylbenzyl)-2-[(R)-1-hydroxymethyl-3- <10(methylthio)propylamino]-5-nitrobenzamideN-(benzofuran-2-ylmethyl)-2-(cis-4-hydroxy- <10cyclohexylamino)-5-nitrobenzamide2-(cis-4-formamidocyclohexylamino)-N-(3,4- <10dimethoxybenzyl)-5-nitrobenzamide2-[1-[1,3-bis(tert-butoxycarbonyl)amidino]-piperidin-4- <10ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide2-(1-amidinopiperidin-4-ylamino)-N-(3,4-dimethoxybenzyl)- <105-nitrobenzamide hydrochloride 5-bromo-N-(3-chloro-4-methoxybenzyl)-2-<10 (cyclopentylamino)benzamide hydrochloride2-[(1S,2R)-2-carbamoyl-2-hydroxypropyl-amino]-N-(3,4- <10dimethoxybenzyl)-5-nitro-benzamide2-(cis-4-hydroxycyclohexylamino)-N-[3-methoxy-4-(2- <10methoxyethoxy)benzyl]-5-nitrobenzamideN-(4-cyclobutylmethoxy-3-methoxybenzyl)-2-[2-hydroxy-1- <10(hydroxymethyl)ethylamino]-5-nitrobenzamide(S)-N-(3,4-dimethoxybenzyl)-2-[1-(formamidomethyl)-2- <10hydroxyethylamino]-5-nitrobenzamide

[0208] As shown in the above Table 1, the compounds (1) of the presentinvention have superior inhibitory activity against cGMP-PDE.

[0209] Test Method 2: The Effect on Erection Function

[0210] (a) Effect of Test Compound on Nitroprusside or Ach-InducedRelaxation in Isolated Rat Corpora Cavernosa.

[0211] Male SD rats were anesthetized with sodium pentobarbital 50 mg/kgintraperitoneally, and the corpora cavernosa was excised. The tunicaalbuginea was dissected according to the methods described by Italianoet al. (Pharmacological Research, 30, No.4, 1994) and used for in vitropharmacological study. The erectile tissue strip was placed in a 25 mlorgan bath containing Krebs-Ringer solution. The bath was maintained at37° C. and bubbled with 95% O₂ and 5% CO₂. The strip was stretched witha resting force of 0.25 g, and isometric contraction were recorded viaforce development transducer on a recorder.

[0212] The strip was equilibrated in the Krebs-Ringer solution for about60 minutes, and preconstructed by 0.1 mM norepinephrine to ascertain theresponsibility of each preparation. The strip was washed several times,and then constricted by 0.1 mM norepinephrine. After getting stableconstrictile response to norepinephrine, the first dose-response curvefor sodium nitroprusside or Ach(acetylcholine) was obtained. Afterwashing a few times for 60 minutes, the strip was constricted bynorepinephrine again, and the second dose-response curve for sodiumnitroprusside or Ach was obtained. The test compound, i.e.,(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamidewhich was selected as a representative compound of this invention wasadded 30 minutes before adding norepinephrine. Relaxant responseelicited by 10 μM nitroprusside was 20% in control preparation, but thisrelaxant response increased to 32% in the presence of the test compound(5×10⁻⁸ M).

[0213] Said compound at 5×10⁻⁸ M also potentiated Ach-induced relaxationof corpora cavernosa. 100 μM Ach-induced relaxant response to thecontractile response induced by 10⁻⁴ M norepinephrine was only 5.0% incontrol preparation, but this relaxant response to Ach increased to18.0% in the presence of said compound (5×10⁻⁸ M).

[0214] (b) Effect of Test Compounds on the Relaxation Elicited byElectrical Field Stimulation in Rabbit Corpora Cavernosa.

[0215] The rabbit erectile tissue strip prepared according to the methoddescribed by Italiano et al. (Pharmacological Research, 30, No4, 1994)was placed 25 ml organ bath containing Krebs-Ringer solution. The bathwas maintained at 37° C. and bubbled with 95% O₂ and 5% CO₂. Thesolution also contained atropine (1μM) and guanethidine (50 μM). Theerectile tissue strip was stretched with a resting force of 0.25 g, andisometric contraction were recorded via force development transducer ona recorder. The bipolar platinum electrode connected to the electricstimulator was placed around the strip.

[0216] The strip was equilibrated in the Krebs-Ringer solution for about60 minutes and preconstructed by 0.1 mM norepinephrine to ascertain theresponsibility of each preparation. The strip was washed several times,and then constricted by 0.1 mM norepinephrine. After getting stablecontractile response to norepinephrine, the first electrical fieldstimulation (1 to 30 Hz, 20V, 0.5 msec duration, 90 sec interval) wasdelivered. 30 minutes after adding the tested compound, the secondelectrical field stimulation was delivered.

[0217] The compounds i.e.,N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamideand(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nitrobenzamidewhich were selected as representative compounds of this invention, at5×10⁻⁸ M potentiated relaxation of corpora cavernosa elicited byelectrical field stimulation in rabbit corpora cavernosa.

[0218] Relaxant response elicited by 30 Hz was only 70% in controlpreparation, but this relaxant response increased to 100% in thepresence of 5×10⁻⁸ M said compounds.

[0219] (c) Male beagle weighing 8.0-12.0 kg were anesthetized withpentobarbital sodium (35 mg/kg, i.v.). After tracheotomy, the animal wasartificially ventilated using a volume-cycled ventilator. The femoralartery was cannulated for continuous blood pressure and heart ratemonitoring. The femoral vein was cannulated for maintenance ofanesthesia and administration of tested compound.

[0220] Either the left or right cavernous nerve was exposedposterolaterally to the prostate and a cuff electrode was placed aroundthe nerve for electrical stimulation. A 21-gauge butterfly needle wasplaced in the corpus cavernousum and connected to a pressure transducerfor intracavernous pressure. After a period of stabilization of allparameters, erection was induced by cavernous nerve electricallystimulation (7 Hz, 10 V) and the following was measured: the duration ofdetumescence (time (T75) from cessation of stimulation to 75% reductionof intracavernous pressure). The test compounds, i.e.,N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamideand(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nitrobenzamidewere each dissolved in 50% PEG400. As shown in Table 2, T75 after thecessation of electrical stimulation was prolonged by the administrationof the compounds (0.1 mg/kg, i.v.) which were selected as representativecompounds of this invention. TABLE 2 mean of prolongation of testcompounds T75 (second) N-(3,4-dimethoxybenzyl)-2-(cis-4- 52hydroxycyclohexylamino)-5-nitrobenzamide(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- 44methylethylamino)-5-nitrobenzamide

[0221] Test Method 3: Toxicities of Compound (I)

[0222] Test on the toxicity by repetitive oral administration of thecompounds, i.e.,N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamideand(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamidewhich were selected as representative compounds of this invention, in SDrat was conducted. The dead at dose of 32 mg/kg once a day for 14consecutive days could not be observed.

[0223] The compound (1) or its salt can be administered alone or in aform of a mixture, preferably, with a pharmaceutical vehicle or carrier.

[0224] The active ingredient of this invention can be used in a form ofa pharmaceutical preparation, for example, in solid, semisolid or liquidform, which contains a compound (I), as an active ingredient, inadmixture with an organic or inorganic carrier or excipient suitable forexternal, enteral, intravenous, intramuscular, parenteral or intramucousapplications. The active ingredient may be compounded, for example, withthe conventional non-toxic, pharmaceutically acceptable carriers forointment, cream, plaster, tablets, pellets, capsules, suppositories,solution (saline, for example), emulsion, suspension (olive oil, forexample), aerosols, pills, powders, syrups, injections, troches,cataplasms, aromatic waters, lotions, buccal tablets, sublingualtablets, nasal drops and any other form suitable for use. The carrierswhich can be used are water, wax, glucose, lactose, gum acacia, gelatin,mannitol, starch paster, magnesium trisilicate, talc, corn starch,keratin, paraffin, colloidal silica, potato starch, urea and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form, and in addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. The activecompound is included in a pharmaceutical composition in an effectiveamount sufficient to produce the desired effect upon the process orcondition of the diseases.

[0225] The active ingredient may be compounded into, for example,preparations for oral application, preparations for injection,preparations for external application, preparations for inhalation,preparations for application to mucous membranes (oral mucous membrane,fascia penis, facies urethralis penis, etc.).

[0226] Mammals which may be treated by the present invention includelivestock mammals such as cows, horses, etc., domestic animals such asdogs, cats, rats, etc. and humans, preferably humans.

[0227] While the dosage of therapeutically effective amount of acompound (I) varies from and also depends upon the age and condition ofeach individual patient to be treated, in case of the systemicadministration, a daily dose of about 0.01-1000 mg, preferably 0.1-500mg and more preferably 0.5-100 mg of the active ingredient is generallygiven for treating the diseases, and an average single dose of about0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg isgenerally administered. Daily doses for chronic administration in humanswill be in the range of about 0.3 mg/body to 1,000 mg/body.

[0228] The patents, patent applications and publications cited hereinabove are incorporated by reference. (to be continued on the next page)

BEST MODE FOR CARRYING OUT THE INVENTION

[0229] The following Examples are given only for the purpose ofillustrating the present invention in more detail.

[0230] Preparation 1

[0231] A mixture of 2-fluoro-5-nitrobenzoic acid (1.00 g),(1,3-benzodioxol-5-ylmethyl)amine (980 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.55 g)and 1-hydroxybenzotriazole (1.09 g) in anhydrous dimethylformamide (10mL) was stirred for 40 hours at ambient temperature. The mixture waspartitioned between water and ethyl acetate. The separated organic layerwas washed with an aqueous saturated sodium bicarbonate solution,1N-hydrochloric acid, water and brine. Then, the resultant was driedover magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether to give2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellowpowders (1.48 g).

[0232] NMR (DMSO-d₆, δ): 4.38 (2H, d, J=7 Hz), 5.99 (2H, s), 6.80-6.98(3H, m), 7.62 (1H, m), 8.39 (2H, m), 9.12 (1H, br)

[0233] Mass m/z: 317 (M⁺)

EXAMPLE 1(1)

[0234] To a solution of2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) inanhydrous pyridine (3 mL) was added trans-4-aminocyclohexanol (81.4 mg),and the mixture was stirred for 15 hours at ambient temperature, andthen for 3 hours at 60° C. The mixture was partitioned between ethylacetate and water. The separated organic layer was washed with water andbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas subjected to a silica gel column chromatography eluting with amixture of chloroform and methanol (20:1). The eluent was concentratedand the residue was triturated with diisopropyl ether to give2-(trans4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (164 mg).

[0235] NMR (CDCl₃, δ): 1.38-1 .60 (4H, br), 2.00-2.24 (4H, br), 3.44(1H, br), 3.76 (1H, br), 4.49 (2H, d, J=7 Hz), 5.97 (2H, s), 6.44 (1H,br), 6.67 (1H, d, J=8 Hz), 6.80 (3H, m), 8.14 (1H, dd, J=4, 8 Hz), 8.29(1H, d, J=4 Hz), 8.86 (1H br)

[0236] Mass m/z: 412 (M⁺).

EXAMPLE 1(2)

[0237] To a solution of2-(trans-4-hydroxycyclohexylarino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(100 mg) in dichloromethane (3 mL) and acetonitrile (0.4 mL) were addedtetrapropylammonium perruthenate (4.25 mg), 4-methylmorpholine N-oxide(42.5 mg) and molecular sieves (4 Å, 0.2 g). The resulting mixture wasstirred for 2 hours at ambient temperature. The mixture was subjected toa silica gel chromatography eluting with ethyl acetate to give5-nitro-2-(4-oxocyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(92 mg) as a solid substance.

[0238] NMR (DMSO-d₆, δ): 1.70-1.87 (2H, m), 2.12-2.53 (4H, m), 2.49-2.60(2H, m), 4.06 (1H, m), 4.35 (2H, d, J=6 Hz), 5.98 (2H, s), 6.75-6.91(3H, m), 7.03 (1H, d, J=9 Hz), 8.16 (1H, dd, J=2, 9 Hz), 8.63 (1H, d,J=2 Hz), 9.22 (1H, d, J=8 Hz), 9.36 (1H, t, J=6 Hz)

[0239] Mass m/z: 410 (M⁺−1).

EXAMPLE 2(1)

[0240](S)-2-[1-(Hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(69 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (72 mg) and(S)-2-amino-1-butanol (42.4 mg) in a manner similar to Example 1(1).

[0241] mp: 128-130° C.

[0242] NMR (DMSO-d₆, δ): 0.92 (3H, t, J=7 Hz), 1.49 (1H, m), 1.67 (1H,m), 3.4-3.65 (3H, m), 4.36 (2H, d, J=7 Hz), 4.92 (1H, t, J=6 Hz), 5.98(2H, s), 6.75-6.93 (4H, m), 8.09 (1H, dd, J=2, 8 Hz), 8.59 (1H, d, J=2Hz), 9.16 (1H, d, J=7 Hz), 9.31 (1H, t, J=6 Hz).

EXAMPLE 2(2)

[0243] To a solution of(S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(127 mg) in 1,2-dichloroethane (4 mL) and carbontetrachloride (2 mL) wasadded triphenylphosphine (215 mg), and the mixture was stirred for anhour under reflux. The solvent was evaporated in vacuo and the residuewas subjected to a silica gel column chromatography eluting with amixture of chloroform and ethyl acetate (9:1) to give(S)-2-[1-(chloromethyl)propylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(71 mg) as a solid substance.

[0244] NMR (DMSO-d₆, δ): 0.92 (3H, t, J=7 Hz), 1.52-1.80 (2H, m), 3.82(2H, m), 3.99 (1H, m), 4.36 (2H, d, J=6 Hz), 5.99 (2H, s), 6.78-6.92(3H, m), 6.98 (1H, d, J=9 Hz), 8.13 (1H, dd, J=2, 9 Hz), 8.61 (7H, d,J=2 Hz), 9.19 (1H, d, J=8 Hz), 9.36 (1H, t, J=6 Hz)

[0245] Mass m/z: 404 (M⁺−1).

EXAMPLE 3(1)

[0246]2-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(108 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) and2-amino-1,3-propanediol (42.9 mg) in a manner similar to Example 1 (1).

[0247] NMR (DMSO-d₆, δ): 3.48-3.68 (5H, br), 4.34 (2H, d, J=7 Hz), 4.93(2H, t, J=7 Hz), 5.98 (2H, s), 6.78-6.96 (4H, m), 8.12 (1H, dd, J=4 Hz,8 Hz), 8.58 (1H, d, J=4 Hz), 9.28 (2H, br)

[0248] Mass m/z: 388 (M⁺).

EXAMPLE 3(2)

[0249]2-[2-Chloro-1-(chloromethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(36 mg) was obtained from2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(101 mg) in a manner similar to Example 2(2).

[0250] NMR (DMSO-d₆, δ); 3.89 (4H, d, J=6 Hz), 4.36 (2H, d, J=5 Hz),4.47 (1H, m), 5.99 (2H, s), 6.78-6.93 (3H, m), 7.08 (1H, d, J=9 Hz),8.16 (1H, dd, J=2, 9 Hz), 8.64 (1H, d, J=2 Hz), 9.39 (1H, t, J=5 Hz),9.44 (1H, d, J=8 Hz)

[0251] Mass m/z : 424, 426 (M⁺−1).

EXAMPLE 3(3)

[0252] To a solution ofN-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide(134 mg) in a mixture of dichloromethane (1 mL) and pyridine (1 mL) wasadded triphosgene (49.1 mg) at −78° C. Then, the resulting mixture wasstirred for an hour at ambient temperature. The mixture was diluted withethyl acetate and washed successively with diluted ammonium chloride,water and brine. The organic layer was dried over sodium sulfate andevaporated in vacuo. The residue was subjected to a silica gel columnchromatography eluting with a mixture of chloroform and ethyl acetate(7:3) to giveN-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5-ylamino)benzamide(129 mg) as a solid substance.

[0253] NMR (CDCl₃, δ): 3.88 (3H, s), 3.90 (3H, s), 4.21 (1H, m), 4.49(2H, m), 4.53 (2H, d, J=8 Hz), 4.69 (2H, m), 6.60-6.72 (2H, m),6.84-6.96 (3H, m), 8.23 (1H, dd, J=2, 9 Hz), 8.39 (1H, d, J=2 Hz), 9.44(1H, m)

[0254] Mass m/z: 430 (M⁺−1).

EXAMPLE 3(4)

[0255] To a solution ofN-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide(117 mg) in dichloromethane (5.0 mL) were added 2,2-dimethoxypropane(0.36 mL) and 4-toluenesulfonic acid (10 mg), and the mixture wasstirred for 30 minutes under reflux. The resulting mixture was dilutedwith ethyl acetate and washed successively with diluted sodiumbicarbonate and brine. The organic layer was dried over sodium sulfateand evaporated in vacuo. The residue was triturated with diethyl etherto giveN-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5-ylamino)-5-nitrobenzamide(105 mg) as a solid substance.

[0256] NMR (CDCl₃, δ): 1.50 (3H, s), 1.51 (3H, s), 3.68 (1H, m), 3.83(2H, dd, J=6, 12 Hz), 3.88 (3H, s), 3.90 (3H, s), 4.15 (2H, dd, J=4, 12Hz), 4.52-4.57 (2H, m), 6.66 (1H, d, J=9 Hz), 6.83-6.95 (3H, m), 6.94(1H, m), 8.16 (1H, dd, J=2, 9 Hz), 8.39 (1H, d, J=2 Hz)

[0257] Mass m/z: 446 (M⁺+1).

EXAMPLE 4(1)

[0258](S)-2-[1-(tert-Butoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(131 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (107 mg) and(S)-alanine tert-butyl ester hydrochloride (85.5 mg) in a manner similarto Example 1(1).

[0259] NMR (DMSO-d₆, δ); 1.41 (3H, d, J=7 Hz), 1.43 (9H, s), 4.30-4.38(3H, m), 5.99 (2H, s), 6.71-6.93 (4H, m), 8.17 (1H, dd, J=2, 9 Hz), 8.62(1H, d, J=2 Hz), 9.34-9.43 (2H, m)

[0260] Mass m/z: 442 (M⁺−1)

EXAMPLE 4(2)

[0261] To a solution of(S)-2-[1-(tert-butoxycarbonyl)ethylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(104 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.6mL), and the mixture was stirred for 2 hour at ambient temperature. Theresulting mixture was evaporated in vacuo and the residue was trituratedwith diethyl ether to give(S)-2-(1-carboxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(76 mg) as a solid substance.

[0262] NMR (DMSO-d₆, δ); 1.43 (3H, d, J=7 Hz), 4.31-4.42 (3H, m), 5.99(2H, s), 6.73-6.93 (4H, m), 8.15 (1H, dd, J=2, 9 Hz), 8.61 (1H, d, J=2Hz), 9.32-9.41 (2H, m)

[0263] Mass m/z: 386 (M⁺−1)

EXAMPLE 5

[0264]2-(trans-2-Hydroxycyclopentylamino)-S-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(107 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) andtrans-2-aminocyclopentanol (47.7 mg) in a manner similar to Example 1(1).

[0265] NMR (CDCl₃, δ): 1.55-1.75 (2H, m), 1.76-1.95 (2H, m), 2.00-2.13(1H, m), 2.26-2.38 (1H, m), 3.78 (1H, br), 4.16 (1H, br), 4.48 (2H, d,J=7 Hz), 5.96 (2H, s), 6.50 (1H, br) 6.77-6.90 (4H, m), 8.13 (1H, dd,J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 8.86 (1H, br)

[0266] Mass m/z: 398 (M⁺).

EXAMPLE 6

[0267]2-(2-Hydroxy-1,1-dimethylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(80.0 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) and2-amino-2-methyl-1-propanol(84.0 mg) in a manner similar to Example1(1).

[0268] NMR (CDCl₃, δ) 1.47 (6H, s), 1.88 (1H, t, J=7 Hz), 3.70 (2H, d,J=7 Hz), 4.50 (2H, d, J=7 Hz), 5.97 (2H, s), 6.45 (1H, br), 6.76-6.95(4H, m), 8.10 (1H, dd, J=4, 8 Hz), 8.28 (1H, d, J=4 Hz), 9.13 (1H, br)

[0269] Mass m/z: 388 (M⁺).

EXAMPLE 7

[0270](R)-2-(2-Hydroxy-1-methylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(65 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (93 mg) and(R)-2-amino-1-propanol(44 mg) in a manner similar to Example 1(1).

[0271] mp: 166-168° C.

[0272] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 3.46 (2H, m), 3.76 (1H,m), 4.33 (2H, d, J=7 Hz), 4.98 (1H, t, J=6 Hz), 5.98 (2H, s), 6.75-6.93(4H, m), 8.11 (1H, dd, J=2, 8 Hz), 8.58 (1H, d, J=2 Hz), 9.15 (1H, d,J=7 Hz), 9.29 (1H, t, J=6 Hz).

EXAMPLE 8

[0273]5-Nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(2-thiazolylamino)benzamide (28mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (70 mg) and2-aminothiazole (26.4 mg) in a manner similar to Example 1(1).

[0274] NMR (DMSO-d₆, δ): 4.43 (2H, d, J=5 Hz), 5.99 (1H, s), 6.81-6.91(2H, m), 6.96 (1H, s), 7.27 (1H, d, J=4 Hz), 7.47 (1H, d, J=4 Hz), 8.39(1H, dd, J=2, 9 Hz), 8.70-8.6 (2H, m), 9.70 (1H, t, J=5 Hz)

[0275] Mass m/z : 397 (M⁺−1).

EXAMPLE 9

[0276](R)-2-(1-Ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(55.8 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (72 mg) and(R)-2-amino-1-butanol (0.045 mL) in a manner similar to Example 1(1).

[0277] NMR (DMSO-d₆, δ): 0.89 (3H, t, J=7 Hz), 1.49 (1H, m), 1.66 (1H,m), 3.38-3.45 (3H, m), 4.34 (2H, d, J=6 Hz), 4.92 (1H, t, J=5 Hz), 5.98(2H, s), 6.78-6.92 (4H, m), 8.09 (1H, dd, J 2, 9 Hz), 8.58 (1H, d, J=2Hz), 9.16 (1H, d, J=8 Hz), 9.30 (1H, t, J=6 Hz)

[0278] Mass m/z: 386 (M⁺−1).

EXAMPLE 10

[0279](R)-5-Nitro-2-(tetrahydro-3-furanylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(76 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80 mg) and(R)-3-aminotetrahydrofuran p-toluenesulfonate (78.2 mg) in a mannersimilar to Example 1 (1).

[0280] NMR (DMSO-d₆, δ): 1.79 (1H, m), 2.31 (1H, m), 3.60 (1H, m),3.71-3.94 (3H, m), 4.29 (1H, m), 4.37 (2H, d, J=6 Hz), 5.99 (2H, s),6.81 (1H, d, J=8 Hz), 6.87-6.95 (3H, m), 8.17 (1H, m), 8.63 (1H, d, J=2Hz), 9.26 (1H, d, J=8 Hz), 9.38 (1H, t, J=6 Hz)

[0281] Mass m/z: 384 (M⁺−1).

EXAMPLE 11

[0282](S)-2-[2-Hydroxy-1-(methoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(73 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (89 mg) and(S)-serine methyl ester hydrochloride (69.7 mg) in a manner similar toExample 1 (1).

[0283] NMR (DMSO-d₆, δ): 3.67 (3H, s), 3.74 (1H, m), 3.91 (1H, m), 4.36(2H, d, J=6 Hz), 4.54 (1H, m), 5.34 (1H, t, J=5 Hz), 5.99 (2H, s),6.76-6.93 (4H, m), 8.11 (1H, dd, J=2, 9 Hz), 8.62 (1H, d, J=2 Hz), 9.34(1H, t, J=6 Hz), 9.57 (1H, d, J=8 Hz)

[0284] Mass m/z :416 (M⁺−1).

EXAMPLE 12

[0285](R)-2-[1-(Methoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(85 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (92 mg) and(R)-alanine methyl ester hydrochloride (64.6 mg) in a manner similar toExample 1(1).

[0286] NMR (DMSO-d₆, δ): 1.46 (3H, d, J=7 Hz), 3.69 (3H, s), 4.36 (2H,d, J=5 Hz), 4.53 (1H, m), 5.99 (2H, s), 6.75-6.93 (4H, m), 8.14 (1H, dd,J 2, 9 Hz), 8.63 (1H, d, J=2 Hz), 9.34-9.44 (2H, m)

[0287] Mass m/z 400 (M⁺−1).

EXAMPLE 13

[0288]2-(2,3-Dihydro-1H-inden-2-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(82.7 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (90 mg) and2-aminoindan hydrochloride (57.6 mg) in a manner similar to Example1(1).

[0289] NMR (DMSO-d₆, δ): 2.86 (2H, m), 3.43 (2H, m), 4.32 (2H, d, J=6Hz), 4.52 (1H, m), 5.99 (2H, s), 6.75-6.79 (3H, m), 6.99 (1H, d, J=9Hz), 7.15-7.20 (2H, m), 7-21-7.29 (2H, m), 8.17 (1H, dd, J=2, 9 Hz),8.61 (1H, d, J=2 Hz), 9.26-9.35 (2H, m)

[0290] Mass m/z: 430 (M⁺−1).

EXAMPLE 14

[0291]2-(trans-2-Aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(73.5 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (96 mg) andtrans-1,2-diaminocyclohexane (0.072 mL) in a manner similar to Example1(1).

[0292] NMR (DMSO-d₆, δ): 1.16-1.41 (4H, m), 1.61-1.71 (2H, m), 1.87-2.00(2H, m), 2.84 (1H, m), 3.46 (1H, m), 4.36 (2H, m), 4.59 (1H, d, J=4 Hz),5.98 (2H, s), 6.78-6.92 (3H, m), 7.01 (1H, d, J=9 Hz), 8.10 (1H, dd,J=2, 9 Hz), 8.60 (1H, d, J=2 Hz), 9.10 (1H, d, J=8 Hz), 9.33 (1H, br)

[0293] Mass m/z: 413 (M⁺+1).

EXAMPLE 15

[0294] 2-[(1R,2R)-2-Hydroxy-1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(81.8 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (93 mg) and(R)-threoninol (61.4 mg) in a manner similar to Example 1 (1).

[0295] NMR (DMSO-d₆, δ): 1.07 (3H, d, J=7 Hz), 3.37-3.56 (3H, m), 4.03(1H, m), 4.34 (2H, d, J=5 Hz), 4.83 (1H, m), 4.97 (1H, d, J=5 Hz), 5.99(2H, s), 6.75-6.94 (4H, m), 8.09 (1H, dd, J=2, 9 Hz), 8.56 (1H, d, J=2Hz), 9.23-9.30 (2H, m)

[0296] Mass m/z: 402 (M⁺−1).

EXAMPLE 16

[0297]2-[2-(Tetrahydro-2-oxo-3-furanyl)amino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(22.8 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (54.8 mg) and2-amino-γ-butyrolactone hydrobromide (37.6 mg) in a manner similar toExample 1(1).

[0298] NMR (DMSO-d₆, δ): 2.15-2.3 (1H, m), 2.7-2.86 (1H, m), 4.29 (1H,m), 4.35 (2H, d, J=5 Hz), 4.42 (1H, t, J=7 Hz), 4.83 (1H, m), 4.97 (1H,d, J=5 Hz), 5.99 (2H, s), 6.75-6.91 (3H, m), 6.97 (1H, d, J=9 Hz), 8.13(1H, dd, J=2, 9 Hz), 8.61 (1H, d, J=2 Hz), 9.24 (1H, d, J=8 Hz), 9.38(1H, t, J=6 Hz)

[0299] Mass m/z: 398 (M⁺−1).

EXAMPLE 17

[0300]2-(tert-Butylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(94.3 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) andtert-butylamine (115 mg) in a manner similar to Example 1 (1).

[0301] NMR (CDCl₃, δ): 1.48 (9H, s), 4.48 (2H, d, J=7 Hz), 5.96 (2H, s),6.47 (1H, br), 6.77-6.90 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.29 (1H, d,J=4 Hz), 9.08 (1H, br)

[0302] Mass m/z: 370 (M⁺).

EXAMPLE 18

[0303]2-[1-(Ethoxycarbonyl)piperidin-4-ylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(204 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) andethyl 4-amino-1-piperidinecarboxylate (122 mg) in a manner similar toExample 1(1).

[0304] NMR (CDCl₃, δ): 1.28 (3H, t, J=7 Hz), 1.50-1.70 (2H, br),1.97-2.10 (2H, br), 3.06-3.23 (2H, br), 3.58-3.70 (1H, br), 3.95-4.10(2H, br), 4.16 (2H, q, J=7 Hz), 4.48 (2H, d, J=7 Hz), 5.98 (2H, s), 6.50(1H, br), 6.69 (1H, d, J=8 Hz), 6.77-6.90 (3H, m), 8.16 (1H, dd, J=4, 8Hz), 8.32 (1H, d, J=4 Hz), 9.00 (1H, br)

[0305] Mass m/z: 469 (M⁺).

EXAMPLE 19

[0306]2-(1-Benzylpiperidin-4-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(123 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and4-amino-1-benzylpiperidine (122 mg) in a manner similar to Example 1(1).

[0307] NMR (CDCl₃, δ): 1.63-1.78 (2H, br), 1.96-2.08 (2H, br), 2.17-2.33(2H, br), 2.75-2.90 (2H, br), 3.48 (1H, br), 3.55 (2H, s), 4.50 (2H, d,J=7 Hz), 5.97 (2H, s), 6.40 (1H, br), 6.65 (1H, d, J=8 Hz), 6.77-6.88(3H, m), 7.23-7.38 (5H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.28 (1H, d, J=4Hz), 8.93 (1H, br)

[0308] Mass m/z: 489 (M⁺).

EXAMPLE 20

[0309]2-[2-Hydroxy-1,1-bis(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(14.6 mg) was obtained as brown powders from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) and2-amino-2-(hydroxymethyl)-1,3-propanediol (114 mg) in a manner similarto Example 1(1).

[0310] NMR (DMSO-d₆, δ): 3.65 (6H, d, J=7 Hz), 4.33 (2H, d, J=7 Hz),4.84 (3H, t, J=7 Hz), 5.98 (2H, s), 6.79-6.93 (3H, m), 7.25 (1H, d, J=8Hz), 8.02 (1H, dd, J=4, 8 Hz), 8.48 (1H, d, J=4 Hz), 9.18 (1H, br), 9.29(1H, br)

[0311] Mass m/z: 418 (M⁺).

EXAMPLE 21

[0312]2-[2-Hydroxy-1-(hydroxymethyl)-1-methylethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(115 mg) was obtained from2-fluoro-5-nitro-N-(1.,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and2-methyl-2-amino-1,3-propanediol (149 mg) in a manner similar to Example1 (1).

[0313] NMR (DMSO-d₆, δ): 1.26 (3H, s), 3.45-3.60 (4H, m), 4.32 (2H, d,J=7 Hz), 5.00 (2H, t, J=7 Hz), 5.98 (2H, s), 6.78-6.90 (3H, m), 7.08(1H, d, J=8 Hz), 8.03 (1H, dd, J=4, 8 Hz), 8.51 (1H, d, J=4 Hz), 9.24(1H, br), 9.33 (1H, br)

[0314] Mass m/z: 402 (M⁺).

EXAMPLE 22

[0315]2-(tert-Butoxyamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(56.0 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and2-tert-butoxyamine (118 mg) in a manner similar to Example 1(1).

[0316] NMR (CDCl₃, δ): 1.35 (9H, s), 4.51 (2H, d, J=7 Hz), 5.97 (2H, s),6.48 (1H, br), 6.78-6.86 (3H, m), 7.28 (1H, d, J=8 Hz), 8.19 (1H, dd,J=4, 8 Hz), 8.29 (1H, d, J=4 Hz)

[0317] Mass m/z: 386 (M⁻).

[0318] Preparation 23

[0319] To a solution of 4-amino-1-cyclohexanecarboxylic acid (500 mg) indichloromethane (20 mL) and methanol (10 mL) was added 10% hexanesolution of trimethylsilyldiazomethane (638 mg), and the mixture wasstirred for 21 hours at ambient temperature. The mixture was evaporatedin vacuo to give methyl 4-amino-1-cyclohexanecarboxylate as a colorlessoil (544 mg).

[0320] NMR (CDCl₃, δ): 1.27-1.73 (6H, br), 1.88-2.08 (2H, br), 2.48 (1H,m), 2.85 (1H, m), 3.67 and 3.68 (3H, s).

EXAMPLE 23(1)

[0321]2-[4-(Methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(381 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (300 mg) andmethyl 4-amino-1-cyclohexanecarboxylate (222 mg) in a manner similar 10to Example 1(1).

[0322] NMR (CDCl₃, δ): 1.70-2.03 (8H, br), 2.52 (1H, br), 3.63 (1H, br),3.71 (3H, s), 4.50 (2H, d, J=7 Hz), 5.97 (2H, s), 6.41 (1H, br), 6.66(1H, m), 6.78-6.87 (3H, m), 8.14 (1H, m), 8.30 (1H, m), 8.86 and 9.08(1H, br)

[0323] Mass m/z: 456 (M⁺).

EXAMPLE 23(2)

[0324] A mixture of2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(269 mg), methanol (10 mL), tetrahydrofuran (10 mL) and 1N-sodiumhydroxide solution (5 mL) was 20 stirred for an hour at 60° C. Themixture was acidified with 1N-hydrochloric acid to pH 4 and the organicsolvent was removed by evaporation. The aqueous layer was diluted withwater and extracted with chloroform. The extract was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether to give2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (253 mg).

[0325] NMR (DMSO-d₆, δ): 1.20-2.05 (8H, br), 2.42 (1H, br), 3.77 (1H,br), 4.35 (2H, d, J=7 Hz), 5.96 (2H, s), 6.78-6.95 (4H, m), 8.10 (1H,dd, J=4, 8 Hz), 30 8.60 (1H, d, J=4 Hz), 9.08 and 9.33 (2H, br)

[0326] Mass m/z: 440 (M⁻).

EXAMPLE 23(3)

[0327] To a mixture of2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(80.0 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(52.1 mg), 1-hydroxybenzotriazole (36.7 mg) in dimethylformamide (1 mL)was added 28% ammonia solution (10 drops). After stirring for 15 hoursat ambient temperature, the mixture was partitioned between water andethyl acetate. The separated organic layer was washed with an aqueoussaturated sodium bicarbonate solution, water and brine. Then, theresultant was dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by a silica gel column chromatography eluting with10% methanol in chloroform. The obtained product was triturated withdiisopropyl ether to give2-(4-carbamoylcyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (60.0 mg).

[0328] NMR (CDCl₃, δ): 1.18-1.85 (8H, br), 2.22 (1H, br), 3.82 (1H, br),4.37 (2H, d, J=7 Hz), 5.99 (2H, s), 6.70-6.93 (5H, m), 7.23 (1H, br),8.12 (1H, dd, J=4, 8 Hz), 8.62 (1H, d, 3=4 Hz), 9.06 and 9.43 (1H, br),9.33 (1H, br)

[0329] Mass m/z: 439 (M⁺).

EXAMPLE 24(1)

[0330]2-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(539 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (480 mg) andtert-butyl 4-amino-1-piperidinecarboxylate (604 mg) in a manner similarto Example 1(1).

[0331] NMR (CDCl₃, δ): 1.47 (9H, s), 1.57 (2H, br), 2.00 (2H, br), 3.08(2H, br), 3.62 (1H, br), 4.00 (2H, br), 4.49 (2H, d, J=7 Hz), 5.97 (2H,s), 6.50 (1H, br), 6.68 (1H, d, J=8 Hz), 6.82 (3H, m), 8.14 (1H, dd,J-4, 8 Hz), 8.31 (1H, d, J=4 Hz), 9.00 (1H, d, J=8 Hz)

[0332] Mass m/z: 497 (M⁺).

EXAMPLE 24(2)

[0333] To a solution of2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(469mg) in dichloromethane (6 mL) was added trifluoroacetic acid (1.07 g),and the mixture was stirred for 4 hours at ambient temperature. Thereaction mixture was washed with 1N-sodium hydroxide solution, water andbrine. Then, the resultant was dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with diisopropyl etherto give5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (335 mg).

[0334] NMR (DMSO-d₆, δ): 1.34 (2H, br), 1.89 (2H, br), 2.10 (1H, br),2.64 (2H, br), 2.93 (2H, br), 3.65 (1H, br), 4.34 (2H, d, J=7 Hz), 5.98(2H, s), 6.88 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz),9.14 (1H, d, J=8 Hz), 9.34 (1H, br)

[0335] Mass m/z: 399 (M⁺).

EXAMPLE 24(3)

[0336] A mixture of5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(80.0 mg), acetic acid (13.3 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57.7 mg)and 1-hydroxybenzotriazole (40.7 mg) in anhydrous dimethylformamide (1mL) was stirred for 3 hours at ambient temperature. The mixture waspartitioned between water and ethyl acetate. The organic layer wasseparated and washed with an aqueous saturated sodium bicarbonatesolution, water and brine. Then, the resultant was dried over magnesiumsulfate and evaporated in vacuo. The residue was triturated withdiisopropyl ether to give2-(1-acetyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (81.1 mg).

[0337] NMR (DMSO-d₆, δ): 1.27 (1H, br), 1.46 (1H, br), 1.95 (2H, br),2.01 (3H, s), 2.90 (1H, br), 3.23 (1H, br), 3.75 (1H, br), 3.82 (1H,br), 4.17 (1H, br), 4.34 (2H, d, J=7 Hz), 5.98 (2H, s), 6.81-6.90 (3H,m), 6.98 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4Hz), 9.14 (1H, d, J=8 Hz), 9.35 (1H, br)

[0338] Mass m/z: 439 (M⁺).

EXAMPLE 24(4)

[0339] To a mixture of5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(80.0 mg) and 37% formaldehyde solution (192 mg) in methanol (4 mL) wereadded sodium cyanoborohydride (37.9 mg) and acetic acid (4 drops). Afterstirring for 2 hours at ambient temperature, the mixture was partitionedbetween an aqueous saturated sodium bicarbonate solution and chloroform.The organic layer was separated and washed with water and brine. Then,the resultant was dried over magnesium sulfate and evaporated in vacuo.The residue was triturated with diisopropyl ether to give2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (65.0 mg).

[0340] NMR (CDCl₃, δ): 1.53-1.80 (2H, br), 2.04 (2H, br), 2.19 (2H, br),2.32 (3H, s), 2.75 (2H, br), 3.48 (1H, br), 4.48 (2H, br), 5.97 (2H, s),6.41 (1H, br), 6.63 (1H, br), 6.80 (3H, br), 8.13 (1H, br), 8.29 (1H,br), 8.93 (1H, br)

[0341] Mass m/z: 413 (M⁺).

EXAMPLE 24(5)

[0342]2-(1-Formyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(70.0 mg) was obtained from5-nitro-2-(4-piperidinylaminno)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(80.0 mg) and formic acid (10.4 mg) in a manner similar to Example24(3).

[0343] NMR (DMSO-d₆, δ): 1.20-1.48 (2H, br), 1.90-2.08 (2H, br),2.85-2.97 (1H, br), 3.16-3.30 (1H, br), 3.60-3.73 (1H, br), 3;80-3.95(1H, br), 3.98-4.10 (1H, br), 4.34 (2H, d, J=7 Hz), 5.98 (2H, s),6.75-6.93 (3H, m), 7.00 (1H, d, J=8 Hz), 7.99 (1H, s), 8.13 (1H, dd,J=4, 8 Hz), 8.62 (1H, d, J=4 Hz), 9.17 (1H, d, J=8 Hz), 9.35 (1H, br)

[0344] Mass m/z: 425 (M⁺).

EXAMPLE 25

[0345]2-[1-(Hydroxymethyl)cyclopentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(130 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and1-aminocyclopentanemethanol (81.4 mg) in a manner similar to Example 1(1).

[0346] NMR (CDCl₃, δ): 1.66-1.86 (5H, m), 1.96 (4H, m), 3.76 (2H, d, J=7Hz), 4.49 (2H, d, J=7 Hz), 5.97 (2H, s), 6.53 (1H, br), 6.76-6.85 (4H,m), 8.07 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 9.06 (1H, br)

[0347] Mass m/z: 412 (M⁺).

EXAMPLE 26

[0348](S)-2-[1-(Hydroxymethyl)-2-rnethylpropylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(127 mg) was obtained from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and(S)-2-amino-3-methyl-1-butanol (72.9 mg) in a manner similar to Example1(1).

[0349] NMR (CDCl₃, δ): 1.03 (6H, t, J=7 Hz), 1.75 (1H, m), 2.02 (1H, m),3.55 (1H, br), 3.69 (1H, m), 3.83 (1H, m), 4.50 (2H, m), 5.97 (2H, s),6.57 (1H, br), 6.77-6.85 (4H, m), 8.09 (1H, dd, J=4, 8 Hz), 8.29 (1H, d,J=4 Hz), 8.98 (1H, br)

[0350] Mass m/z: 400 (M⁺).

EXAMPLE 27

[0351]2-[1-(Hydroxymethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(203 mg) was prepared from2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (200 mg) and2-amino-1-hexanol (221 mg) in a similar manner to that of Example 1(1)as yellow crystals. mp 112-115° C.

[0352] NMR (DMSO-d₆, δ); 0.85 (3H, t, J=8 Hz), 1.20-1.40 (4H, m), 1.45(1H, m), 1.65 (1H, m), 3.48 (2H, t, J=6 Hz), 3.63 (1H, m), 4.27-4.44(2H, m), 4.92 (1H, t, J=6 Hz), 5.99 (2H, s), 6.81 (1H, d, J=8 Hz),6.86-6.91 (3H, m), 8.10 (1H, dd, J=2, 10 Hz), 8.58 (1H, d, J=2 Hz), 9.13(1H, d, J=8 Hz), 9.30 (1H, t, J=5 Hz).

[0353] Preparation 28

[0354] 2-(Cyclopropylamino)-5-nitrobenzoic acid (238 mg) was obtainedfrom 2-fluoro-5-nitrobenzoic acid (275 mg) and cyclopropylamine (255 mg)in a manner similar to Example 1(1).

[0355] NMR (DMSO-d₆, δ): 0.61 (2H, m), 0.90 (2H, m), 2.69 (1H, m), 7.22(1H, d, J=9 Hz), 8.26 (1H, dd, J=2, 9 Hz), 8.65 (1H, d, J=2 Hz), 8.79(1H, br).

EXAMPLE 28

[0356] N-Benzyl-2-(cyclopropylamino)-5-nitrobenzamide (151 mg) wasobtained from 2-(cyclopropylamino)-5-nitrobenzoic acid (115 mg) andbenzylamine (0.073 mL) in a manner similar to Preparation 1.

[0357] NMR (DMSO-d₆, δ): 0.54 (2H, m), 0.87 (2H, m), 2.62 (1H, m), 4.46(1H, d, J=6 Hz), 7.18 (1H, d, J=9 Hz), 7.22-7.40 (5H, in), 8.22 (1H, m),8.64 (1H, d, J=2 Hz), 9.06 (1H, br), 9.44 (1H, t, J=6 Hz)

[0358] Mass m/z: 310 (M⁺−1).

[0359] Preparation 29

[0360] 2-(2-Hydroxycyclohexylamino)-5-nitrobenzoic acid (291 mg) wasobtained from 2-fluoro-5-nitrobenzoic acid (235 mg) and2-aminocyclohexanol (292 mg) in a manner similar to Example 1(1).

[0361] NMR (DMSO-d₆, δ): 1.15-1.45 (6H, m), 1.58-1.72 (2H, m), 1.88-2.08(2H, m), 3.25-3.35 (3H, m), 4.95 (1H, m), 7.02 (1H, d, J=9 Hz), 8.11(1H, dd, J=2, 9 Hz), 8.64 (1H, d, J=2 Hz), 8.98 (1H, d, J=6 Hz).

EXAMPLE 29

[0362] N-Benzyl-2-(2-hydroxycyclohexylamino)-5-nitrobenzamide (107 mg)was obtained from 2-(2-hydroxycyclohexylamino)-5-nitrobenzoic acid (134mg) and benzylamine (0.068 mL) in a manner similar to Preparation 1.

[0363] NMR (DMSO-d₆, δ): 1.38-1.42 (4H, m), 1.55-1.7 (2H, m), 1.8-2.1(2H, m), 3.3-3.4 (2H, m), 4.43 (2H, d, J=6 Hz), 4.92 (1H, d, J=6 Hz),6.96 (1H, d, J=9 Hz), 7.2-7.38 (5H, m), 8.09 (1H, dd, J=2, 9 Hz), 8.62(1H, d, J=2 Hz), 9.28 (1H, d, J=6 Hz), 9.39 (1H, t, J=6 Hz)

[0364] Mass m/z: 368 (M⁺−1).

[0365] Preparation 30(1)

[0366] To a solution of ethyl 2-amino-5-nitrobenzoate (5.00 g),cyclopentanone (9.00 g) and sodium borohydride (4.05 g) in anhydroustetrahydrofuran (100 mL) was added sulfuric acid (6 mL) under ice-watercooling. The mixture was stirred for 9 hours at 0° C. and then for 15hours at ambient temperature. The mixture was neutraiized with anaqueous saturated sodium bicarbonate solution and extracted with ethylacetate. The extract was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified by asilica gel column chromatography eluting with a mixture of hexane andethyl acetate (5:1). The obtained product was triturated with hexane togive ethyl 2-cyclopentylamino-5-nitrobenzoate as yellow powders (5.94g).

[0367] NMR (CDCl₃, δ): 1.41 (3H, t, J=7 Hz), 1.58-1.90 (6H, m), 2.10(2H, m), 3.96 (1H, m), 4.36 (2H, q, J=7 Hz), 6.70 (1H, d, J=8 Hz), 8.18(1H, dd, J=4, 8 Hz), 8.67 (1H, br), 8.87 (1H, d, J=4 Hz)

[0368] Mass m/z: 279 (M⁺).

[0369] Preparation 30(2)

[0370] 2-Cyclopentylamino-5-nitrobenzoic acid (5.16 g) was obtained asyellow powders from ethyl 2-cylcopentylamino-5-nitrobenzoate (5.94 g) ina manner similar to Example 23(2).

[0371] NMR (DMSO-d₆, δ): 1.47 (2H, m), 1.58-1.78 (4H, br), 2.10 (2H br)4.05 (1H, m) 6.93 (1H, d, J=8 Hz), 8.18 (1H, dd, J=4, 8 Hz), 8.65 (1H,d, J=4 Hz), 8.83 (1H, br)

[0372] Mass m/z: 249 (M⁺).

EXAMPLE 30

[0373] To a mixture of 2-cyclopentylamino-5-nitrobenzoic acid (1.00 g),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g),1-hydroxybenzotriazole (810 mg) in anhydrous dimethylformamide (10 mL)was added (1,3-benzodioxol-5-ylmethyl)amine (725 mg), and the mixturewas stirred for 15 hours at ambient temperature. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated and washed with an aqueous saturated sodium bicarbonatesolution, water and brine. Then, the resultant was dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by a silicagel column chromatography eluting with a mixture of chloroform andmethanol (50:1). The obtained product was triturated with diisopropylether and recrystallized from a mixture of hexane and ethyl acetate togive 2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (1.51 g).

[0374] NMR (CDCl₃, δ): 1.58-1.86 (6H, m), 2.08 (2H, m), 3.90 (1H, m),4.50 (2H, d, J=7 Hz), 5.98 (2H, s), 6.46 (1H, br), 6.68 (1H, d, J=8 Hz),6.83 (3H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 8.86 (1H,br)

[0375] Mass m/z: 382 (M⁺).

EXAMPLE 31

[0376] 2-(Cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide (138 mg)was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoicacid (100 mg) and 4-fluorobenzylamine (60.0 mg) in a manner similar toExample 30.

[0377] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.00-2.15 (2H, m), 3.89 (1H,m), 4.58 (2H, d, J=7 Hz), 6.54 (1H, br), 6.68 (1H, d, J=8 Hz), 7.06 (2H,m), 7.33 (2H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 8.85(1H, br)

[0378] Mass m/z: 356 (M⁺).

EXAMPLE 32

[0379] 2-(Cyclopentylamino)-N-(4-methylbenzyl)-5-nitrobenzamide (130 mg)was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoicacid (100 mg) and 4-methylbenzylamine (58.1 mg) in a manner similar toExample 30.

[0380] NMR (CDCl₃, δ); 1.59-1.85 (6H, m), 2.03-2.15 (2H, m), 2.37 (3H,s), 3.90 (1H, m), 4.55 (2H, d, J=7 Hz), 6.45 (1H, br), 6.67 (1H, d, J=8Hz), 7.18 (2H, d, J=8 Hz), 7.25 (2H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8Hz), 8.27 (1H, d, J=4 Hz), 8.87 (1H, br)

[0381] Mass m/z: 352 (M⁺).

EXAMPLE 33

[0382] 2-(Cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide (138mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and4-methoxybenzylamine (65.8 mg) in a manner similar to Example 30.

[0383] NMR (CDCl₃, δ); 1.59-1.85 (6H, m), 2.00-2.15 (2H, m), 3.82 (3H,s), 3.90 (1H, m), 4.52 (2H, d, J=7 Hz), 6.41 (1H, br), 6.67 (1H, d, J=8Hz), 6.90 (2H, d, J=8 Hz), 7.28 (2H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8Hz), 8.27 (1H, d, J=4 Hz), 8.88 (1H, br)

[0384] Mass m/z: 368 (M⁺).

EXAMPLE 34

[0385]2-(Cyclopentylamino)-5-nitro-N-[4-(trifluoromethyl)benzyl]benzamide (155mg) was obtained as yellow powders from2-(cyclopentylaniino)-5-nitrobenzoic acid (100 mg) and4-(trifluoromethyl)benzylamine (84.0 mg) in a manner similar to Example30.

[0386] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.02-2.14 (2H, m), 3.92 (1H,m), 4.65 (2H, d, J=7 Hz), 6.68 (1H, d, J=8 Hz), 6.69 (1H, br), 7.47 (2H,d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 8.16 (1H, dd, J=4, 8 Hz), 8.37 (1H, d,J=4 Hz), 8.85 (1H, br)

[0387] Mass m/z: 406 (M⁺).

Example 35

[0388] 2-(Cyclopentylamino)-5-nitro-N-(4-nitrobenzyl)benzamide (132 mg)was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoicacid (100 mg) and 4-nitrobenzylamine (90.4 mg) in a manner similar toExample 30.

[0389] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.03-2.15 (2H, m), 3.90 (1H,m), 4.72 (2H, d, J=7 Hz), 6.69 (1H, d, J=8 Hz), 6.90 (1H, br), 7.52 (2H,d, J=8 Hz), 8.16 (1H, dd, J=4, 8 Hz), 8.23 (2H, d, J=8 Hz), 8.42 (1H, d,J=4 Hz), 8.87 (1H, br)

[0390] Mass m/z: 385 (M⁺).

EXAMPLE 36

[0391] 2-(Cyclopentylamino)-N-[4-(dimethylamino)benzyl-5-nitrobenzamide(121 mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and4-(dimethylamino)benzylamine hydrochloride (107 mg) in a manner similarto Preparation 1.

[0392] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.03-2.15 (2H, m), 2.96 (6H,s), 3.91 (1H, m), 4.47 (2H, d, J=7 Hz), 6.32 (1H, br), 6.66 (1H, d, J=8Hz), 6.73 (2H, d, J=8 Hz), 7.23 (2H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8Hz), 8.27 (1H, d, J=4 Hz), 8.87 (1H, br)

[0393] Mass m/z: 383 (M⁺).

EXAMPLE 37

[0394] N-(4-Sulfamoylbenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (162mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and4-sulfamoylbenzylamine hydrochloride (107 mg) in a manner similar toPreparation 1.

[0395] NMR (DMSO-d₆, δ): 1.38-1.52 (2H, m), 1.56-1.74 (4H, m), 1.96-2.10(2H, m), 3.96 (1H, m), 4.50 (2H, d, J=7 Hz), 6.86 (1H, d, J=8 Hz), 7.33(2H, s), 7.50 (2H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 8.15 (1H, d, J=8Hz), 8.67 (1H, d, J=4 Hz), 9.16 (1H, d, J=8 Hz), 9.50 (1H, br)

[0396] Mass m/z: 417 (M⁺).

EXAMPLE 38

[0397] N-(4-Bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (160 mg)was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoicacid (100 mg) and 4-bromobenzylamine (107 mg) in a manner similar toPreparation 1.

[0398] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.03-2.15 (2H, m), 3.92 (1H,m), 4.56 (2H, d, J=7 Hz), 6.61 (1H, br), 6.68 (1H, d, J=8 Hz), 7.23 (2H,d, J=8 Hz), 7.48 (2H, d, J=8 Hz), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d,J=4 Hz), 8.86 (1H, br)

[0399] Mass m/z: 418 (M⁺).

EXAMPLE 39

[0400] 2-(Cyclopentylamino)-N-furfuryl-5-nitrobenzamide (120 mg) wasobtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoic acid(100 mg) and furfurylamine (46.6 mg) in a manner similar to Preparation1.

[0401] NMR (CDCl₃, δ): 1.58-1.90 (6H, br), 2.03-2.18 (2H, br), 3.91 (1H,m), 4.61 (2H, d, J=7 Hz), 6.33 (2H, m), 6.51 (1H, br), 6.69 (1H, d, J=8Hz), 7.40 (1H, s), 8.12 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.82(1H, br)

[0402] Mass m/z: 328 (M⁺).

EXAMPLE 40

[0403] 2-(Cyclopentylamino)-5-nitro-N-(2-thienylmethyl)benzamide (130mg) was obtained as yellow powders from2-cyclopentylamino-5-nitrobenzoic acid (100 mg) and2-thiophenemethylamine (54.3 mg) in a manner similar to Preparation 1.

[0404] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.01-2.17 (2H, m), 3.90 (1H,m), 4.77 (2H, d, J=7 Hz), 6.55 (1H, br), 6.68 (1H, d, 3=8 Hz), 6.98 (1H,m), 7.05 (1H, br), 7.28 (1H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.30 (1H, d,J=4 Hz), 8.81 (1H, br)

[0405] Mass m/z: 344 (M⁺).

EXAMPLE 41

[0406] 2-(Cyclopentylamino)-5-nitro-N-phenethylbenzide (141 mg) wasobtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoic acid(100 mg) and phenethylamine (58.1 mg) in a manner similar to Preparation1.

[0407] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.00-2.15 (2H, m), 2.94 (2H,t, J=7 Hz), 3.68 (2H, m), 3.89 (1H, m), 6.24 (1H, br), 6.65 (1H, d, J=8Hz), 7.28 (3H, m), 7.35 (2H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.19 (1H, d,J=4 Hz), 8.75 (1H, br)

[0408] Mass m/z: 352 (M⁺).

EXAMPLE 42

[0409] 2-(Cyclopentylamino)-5-nitro-N-(3-phenylpropyl) benzamide (120mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and3-phenylpropylamine (64.8 mg) in a manner similar to Preparation 1.

[0410] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 1.94-2.15 (4H, m), 2.74 (2H,t, J=7 Hz), 3.47 (2H, m), 3.89 (1H, m), 6.13 (1H, br), 6.68 (1H, d, J=8Hz), 7.17-7.33 (5H, m), 8.13 (2H, m), 8.83 (1H, br)

[0411] Mass m/z: 366 (M⁺).

EXAMPLE 43

[0412]N-[1(2-Benzimidazolyl)methyl]-2-(cyclopentylamino)-5-nitrobenzamide (132mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and2-(aminomethyl)benzimidazole dihydrochloride hydrate (106 mg) in amanner similar to Preparation 1.

[0413] NMR (DMSO-d₆, δ): 1.40-1.54 (2H, br), 1.54-1.75 (4H, br),1.95-2.13 (2H, br), 3.96 (1H, br), 4.66 (2H, d, J=7 Hz), 6.89 (1H, d,J=8 Hz), 7.14 (2H, br), 7.45 (1H, br), 7.53 (1H, br), 8.14 (1H, dd, J=4,8 Hz), 8.73 (1H, d, J=4 Hz), 9.14 (1H, br), 9.53 (1H, br), 12.32 (1H,br)

[0414] Mass m/z: 378 (M⁺).

EXAMPLE 44

[0415]2-(Cyclopentylamino)-N-(4-hydroxy-3-methoxybenzyl)-5-nitrobenzamide (143mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and4-hydroxy-3-methoxybenzylamine hydrochloride (90.9 mg) in a mannersimilar to Preparation 1.

[0416] NMR (DMSO-d₆, δ): 1.39-1.53 (2H, m), 1.55-1.75 (4H, m), 1.98-2.10(2H, m), 3.76 (3H, s), 3.96 (1H, m), 4.35 (2H, d, J=7 Hz), 6.72 (2H, s),6.85 (2H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 8.88 (1H,s), 9.12 (1H, d, J=8 Hz), 9.28 (1H, br)

[0417] Mass m/z: 384 (M⁺).

EXAMPLE 45

[0418] 2-(Cyclopentylamino)-N-(3,4-dihydroxybenzyl)-5-nitrobenzamide(109 mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and3,4-dihydroxybenzylamine hydrobromide (106 mg) in a manner similar toPreparation 1.

[0419] NMR (DMSO-d₆, δ): 1.38-1.52 (2H, m), 1.54-1.75 (4H, m), 1.97-2.10(2H, m), 3.98 (1H, m), 4.28 (2H, br), 6.57 (1H, m), 6.68 (2H, m), 6.87(1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 8.80(2H, br), 9.20 (1H, d, J=8 Hz), 9.27 (1H, br).

EXAMPLE 46

[0420] 2-(Cyclopentylamino)-N-(3,4-difluorobenzyl)-5-nitrobenzamide (130mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and3,4-difluorobenzylamine (68.6 mg) in a manner similar to Preparation 1.

[0421] NMR (CDCl₃, δ): 1.58-1.87 (6H, m), 2.03-2.14 (2H, m), 3.90 (1H,m), 4.55 (2H, d, J=7 Hz), 6.68 (1H, br), 6.69 (1H, d, J=8 Hz), 7.04-7.22(3H, m), 8.16 (1H, dd, J=4, 8 Hz), 8.37 (1H, d, J=4 Hz), 8.88 (1H, br)

[0422] Mass m/z: 374 (M⁺).

[0423] Preparation 47(1)

[0424] Ethyl 5-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoate (315mg) was obtained as yellow powders from ethyl 2-amino-5-nitrobenzoate(300 mg) and tetrahydro-2H-thiopyran-4-one (746 mg) in a manner similarto Preparation 30(1).

[0425] NMR (CDCl₃, δ): 1.44 (3H, t, J=7 Hz), 1.75-1.89 (2H, m),2.28-2.38 (2H, m), 2.70-2.84 (4H, m), 3.49-3.61 (1H, m), 4.38 (2H, q,J=7 Hz), 6.66 (1H, d, J=8 Hz), 8.19 (1H, dd, J=4, 8 Hz), 8.78 (1H, br),8.87 (1H, d, J=4 Hz)

[0426] Mass m/z: 309 (M⁺).

[0427] Preparation 47(2)

[0428] 5-Nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid (280mg) was obtained as yellow powders from ethyl5-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoate (310 mg) in amanner similar to Preparation 30(2).

[0429] NMR (DMSO-d₆, δ): 1.55-1.70 (2H, m), 2.17-2.28 (2H, br),2.62-2.85 (4H, m), 3.66-3.82 (1H, br), 6.98 (1H, d, J=8 Hz), 8.17 (1H,dd, J=4, 8 Hz), 8.66 (1H, d, J=4 Hz), 8.85 (1H, d, J=8 Hz)

[0430] Mass m/z: 281 (M⁺).

EXAMPLE 47(1)

[0431]5-Nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide(170 mg) was obtained as yellow powders fromS-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid (150 mg) and(1,3-benzodioxol-5-ylmethyl)amine (96.4 mg) in a manner similar toPreparation 1.

[0432] NMR (CDCl₃, δ): 1.75-1.90 (2H, m), 2.27-2.36 (2H, m), 2.70-2.82(4H, m), 3.51 (1H, m), 4.50 (2H, d, J=7 Hz), 5.97 (2H, s), 6.47 (1H,br), 6.64 (1H, d, J=8 Hz), 6.78-6.85 (3H, m), 8.15 (1H, dd, J=4, 8 Hz),8.31 (1H, d, J=4 Hz), 9.02 (1H, br)

[0433] Mass m/z: 414 (M⁺).

EXAMPLE 47(2)

[0434] To a solution of5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide(50.0 mg) in anhydrous dichloromethane (1 mL) was addedm-chloroperbenzoic acid (41.5 mg), and the mixture was stirred for 4hours at ambient temperature. To the mixture were added an aqueoussaturated sodium thiosulfate solution and an aqueous sodium bicarbonatesolution. The resulting precipitates were collected by filtration andwashed with water, methanol and ethyl acetate to give2-(1,1-dioxotetrahydro-2H-thiopyran-4-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (40.0 mg).

[0435] NMR (CDCl₃, δ): 1.88-2.10 (2H, br), 2.20-2.33 (2H, br), 3.04-3.19(2H, br), 3.29-3.43 (2H, br), 3.98 (1H, br), 4.37 (2H, d, J=7 Hz), 5.98(2H, s), 6.79-6.98 (4H, m), 8.17 (1H, m), 8.63 (1H, m), 9.18 (1H, br),9.37 (1H, br)

[0436] Mass m/z: 446 (M⁺).

[0437] Preparation 48(1)

[0438] Methyl 5-cyano-2-(cyclopentylamino)benzoate (2.31 g) was obtainedas yellow powders from methyl 5-cyano-2-aminobenzoate (2.00 g) andcyclopentanone (3.01 mL) in a manner similar to Preparation 30(1).

[0439] NMR (CDCl₃, δ); 1.53-1.86 (6H, br), 2.00-2.14 (2H, br), 3.87 (3H,s), 3.90 (1H, br), 6.71 (1H, d, J=8 Hz), 7.49 (1H, dd, J=4, 8 Hz), 8.19(1H, d, J=4 Hz), 8.34 (1H, br).

[0440] Preparation 48(2)

[0441] A mixture of methyl 5-cyano-2-(cyclopentylamino)benzoate (2.30g), methanol (100 mL) and 1N-sodium hydroxide solution (20 mL) washeated for 2 hours under reflux. The reaction mixture was acidified with1N-hydrochloric acid to pH 4 and the organic solvent was removed byevaporation. The aqueous layer was diluted with water and extracted withethyl acetate. The organic layer was washed with water and brine anddried over magnesium sulfate. Then, the resultant was evaporated invacuo to give 5-cyano-2-(cyclopentylamino)benzoic acid (2.15 g) as paleyellow powders.

[0442] NMR (DMSO-d₆, δ): 1.43 (2H, m), 1.64 (4H, m), 2.03 (2H, m), 3.96(1H, m), 6.89 (1H, d, J=8 Hz), 7.68 (1H, dd, J=4, 8 Hz), 8.09 (1H, d,J=4 Hz), 8.51 (1H, d, J=8 Hz)

[0443] Mass m/z: 229 (M⁺).

[0444] Preparation 48(3)

[0445] To a solution of 5-cyano-2-(cyclopentylamino)benzoic acid (40.0mg) in anhydrous tetrahydrofuran (2 mL) was added 1.5 Mdiisobutylaluminium hydride hexane solution (0.34 mL) under dryice-acetone cooling, and the mixture was stirred for an hour at −78° C.and then for 4 hours at ambient temperature. The reaction was quenchedby addition of methanol and an aqueous saturated ammonium chloridesolution. After stirring at ambient temperature for a half hour, themixture was partitioned with 5% sulfuric acid and chloroform. Theseparated organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by apreparative silica gel chromatography with 10% methanol in chloroform togive 2-(cyclopentylamino)-5-formylbenzoic acid (25.0 mg) as pale orangepowders.

[0446] NMR (CDCl₃, ): 1.55-1.88 (6H, m), 2.06-2.18 (2H, m), 3.97 (1H,m), 6.81 (1H, d, J=8 Hz), 7.92 (1H, dd, J=4, 8 Hz), 8.41 (1H, br), 8.48(1H, d, J=4 Hz), 9.73 (1H, s).

EXAMPLE 48

[0447]2-(Cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5-ylmethyl)benzamide(489 mg) was obtained as yellow powders from2-(cyclopentylamino)-5-formylbenzoic acid (1.00 g) and(1,3-benzodioxol-5-ylmethyl)amine (778 mg) in a manner similar toExample 30.

[0448] NMR (CDCl₃, δ): 1.55-1.87 (6H, br), 2.02-2.15 (2H, br), 3.88 (1H,br), 4.48 (2H, d, J=7 Hz), 5.95 (2H, s), 6.44 (1H, br), 6.75 (1H, d, J=8Hz), 6.77-6.84 (3H, m), 7.74 (1H, d, J=8 Hz), 7.87 (1H, s), 8.70 (1H,br), 9.67 (1H, s)

[0449] Mass m/z: 367 (M⁺).

[0450] Preparation 49

[0451] 5-Cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (534 mg)was obtained from 5-cyano-2-fluorobenzoic acid (300 mg) and(1,3-benzodioxol-5-ylmethyl)amine (0.26 mL) in a manner similar toPreparation 1.

[0452] NMR (DMSO-d₆, δ): 4.37 (2H, d, J=6 Hz), 6.00 (2H, s), 6.80-6.93(3H, m), 7.56 (1H, t, J=9 Hz), 8.04 (1H, m), 8.13 (1H, dd, J=2, 6 Hz),9.03 (1H, t, J=6 Hz)

[0453] Mass m/z: 297 (M⁺−1).

EXAMPLE 49(1)

[0454](R)-5-Cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(145 mg) was obtained from5-cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and(R)-2-amino-1-propanol (0.12 mL) in a manner similar to Example 1(1).

[0455] NMR (DMSO-d₆, δ): 1.13 (3H, d, J=7 Hz), 3.42 (2H, t, J=5 Hz),3.67 (1H, m), 4.32 (2H, d, J=6 Hz), 4.92 (1H, t, J=5 Hz), 5.98 (2H, s),6.77-6.92 (4H, m), 7.60 (1H, dd, J=2, 9 Hz), 8.04 (1H, d, J=2 Hz), 8.73(1H, d, J=8 Hz), 8.99 (1H, t, J=6 Hz)

[0456] Mass m/z: 352 (M⁺−1).

EXAMPLE 49(2)

[0457] To a solution of(R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(76 mg) in ethanol (6 mL) was added IN-sodium hydroxide (0.65 mL), andthe mixture was heated for 6 hours under reflux. The solvent wasevaporated in vacuo. The residue was diluted with ethyl acetate andwashed successively with water and brine. The organic layer was driedover sodium sulfate and evaporated in vacuo. The residue was subjectedto a silica gel column chromatography eluting with a mixture ofchloroform and methanol (9:1) to give (R)-5-carbamoyl-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (27 mg) asa solid substance.

[0458] NMR (DMSO-d₆, δ): 1.13 (3H, d, J=7 Hz), 3.3-3.5 (2H, m), 3.62(1H, m), 4.33 (2H, d, J=5 Hz), 4.86 (1H, t, J=5 Hz), 5.98 (2H, s), 6.73(1H, d, J=9 Hz), 6.77-6.90 (3H, m), 7.04 (1H, br), 7.58 (1H, br), 7.77(1H, dd, J=2, 9 Hz), 8.14 (1H, d, J=2 Hz), 8.30 (1H, d, J=8 Hz), 8.83(1H, t, J=5 Hz)

[0459] Mass m/z: 370 (M⁺−1).

EXAMPLE 50(1)

[0460]5-Cyano-2-(trans-4-hydroxycyclohexylamino)-N-1,3-benzodioxol-5-ylmethyl)benzamide(142 mg) was obtained from5-cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (120 mg) andtrans-4-aminocyclohexanol (139 mg) in a manner similar to Example 1(1).

[0461] NMR (DMSO-d₆, δ): 1.15-1.40 (4H, m), 1.75-1.86 (2H, m), 1.89-2.00(2H, m), 3.35-3.53 (2H, m), 4.31 (2H, d, J=6 Hz), 4.60 (1H, d, J=4 Hz),5.98 (2H, s), 6.79 (1H, dd, J=2, 8 Hz), 6.83-6.92 (3H, m), 7.59 (1H, dd,J=2, 9 Hz), 8.05 (1H, d, J=2 Hz), 8.65 (1H, d, J=7 Hz), 9.01 (1H, t, J=6Hz)

[0462] Mass m/z: 392 (M⁺−1).

EXAMPLE 50(2)

[0463]5-Carbamoyl-2-(trans-4-hydroxycyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide(51 mg) was obtained from5-cyano-2-(trans-4-hydroxycyclohexylamino)-N-(1,3-benzodioxo]-5-ylmethyl)benzamide(71 mg) in a manner similar to Example 49(2).

[0464] NMR (DMSO-d₆, δ): 1.13-1.40 (4H, m), 1.75-1.87 (2H, m), 1.89-2.00(2H, m), 3.3-3.53 (2H, m), 4.33 (2H, d, J=6 Hz), 4.59 (1H, d, J=4 Hz),5.98 (2H, s), 6.74 (1H, d, J=9 Hz), 6.77-6.90 (3H, m), 7.04 (1H, br),7.58 (1H, br), 7.77 (1H, dd, J=2, 9 Hz), 8.13 (1H, d, J=2 Hz), 8.24 (1H,d, J=8 Hz), 8.84 (1H, t, J=6 Hz)

[0465] Mass m/z: 410 (M⁺−1).

[0466] Preparation 51

[0467] To a solution of 2-fluoro-5-nitrobenzoic acid (235 mg) inpyridine (1.5 mL) was added trans-4-aminocyclohexanol (292 mg), and themixture was stirred for 3 hours at 80° C. After evaporation of thesolvent, the residue was dissolved in water and neutralized with1N-hydrochloric acid (1.9 mL). The resulting precipitates were collectedby filtration and washed successively with water and methanol to give2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (279 mg) as asolid substance.

[0468] NMR (DMSO-d₆, δ):1.21-1.46 (4H, m), 1.7-1.90 (2H, m), 1.90-2.08(2H, m), 3.3-3.65 (2H, m), 4.67 (1H, br), 6.98 (1H, d, J=8 Hz) 8.14 (1H,dd, J=2, 8 Hz), 8.66 (1H, d, J=2 Hz), 8.74 (1H, d, J=7 Hz).

EXAMPLE 51

[0469] To a solution of2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) indimethylformamide (2 mL) were added 1-hydroxybenzotriazole (96.4 mg),benzylamine (0.063 mL) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137 mg).The mixture was stirred for 3 hours at 20° C. The resulting mixture wasdiluted with ethyl acetate and washed successively with dilutedhydrochloric acid, aqueous sodium bicarbonate and brine. The organiclayer was dried over sodium sulfate and evaporated in vacuo. Theresulting residue was triturated with methanol to giveN-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (150 mg) asa solid substance.

[0470] mp: 233-234° C.

[0471] NMR (DMSO-d₆, δ): 1.17-1.46 (4H, m), 1.72-1.87 (2H, m), 1.92-2.04(2H, m), 3.4-3.6 (2H, m), 4.42 (2H, d, J=7 Hz), 4.62 (1H, d, J=6 Hz),6.90 (1H, d, J=8 Hz), 7.22-7.39 (5H, m), 8.13 (1H, dd, J=2, 8 Hz), 8.63(1H, d, J=2 Hz), 9.10 (1H, d, J=7 Hz), 9.41 (1H, t, J=6 Hz).

EXAMPLE 52(1)

[0472]2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(173 mg) was obtained as a solid substance from2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) and(1,3-benzodioxol-5-ylmethyl)amine (0.072 mL) in a manner similar toPreparation 1.

[0473] mp: 205-206° C.

[0474] NMR (DMSO-d₆, δ) 1.20-1.45 (4H, m), 1.75-1.87 (2H, m), 1.92-2.02(2H, m), 3.4-3.6 (2H, m), 4.34 (2H, d, J=7 Hz), 4.62 (1H, d, J=6 Hz),5.99 (2H, s), 6.77-6.93 (4H, m), 8.11 (1H, dd, J=2, 8 Hz), 8.60 (1H, d,J=2 Hz), 9.08 (1H, d, J=7 Hz), 9.33 (1H, t, J=6 Hz).

EXAMPLE 52(2)

[0475] To a solution of2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(100 mg), benzoic acid (32.5 mg) and diethyl azodicarboxylate (46.3 mg)in anhydrous tetrahydrofuran (2 mL) was added triphenylphosphine (69.8mg). The mixture was stirred for 4 hours at ambient temperature. Themixture was partitioned between an aqueous saturated sodium bicarbonatesolution and ethyl acetate. The separated organic layer was washed withwater and brine, dried over magnesium sulfate and evaporated in vacuo.The residue was purified by a silica gel column chromatography elutingwith a mixture of hexane and ethyl acetate (5:1 to 3:1). The obtainedproduct was triturated with diisopropyl ether to give2-[cis-4-(benzoyloxy)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide asyellow powders (68.5 mg).

[0476] NMR (CDCl₃, δ): 1.78-2.17 (8H, m), 3.60 (1H, br), 4.52 (2H, d,J=7 Hz), 5.27 (1H, br), 5.96 (2H, s), 6.48 (1H, br), 6.71 (1H, d, J=8Hz), 6.78-6.87 (3H, m), 7.46 (2H, m), 7.58 (1H, m), 8.07 (2H, d, J=8Hz), 8.17 (1H, dd, J=4, 8 Hz), 8.33 (1H, d, J=4 Hz), 9.05 (1H, br)

[0477] Mass m/z: 516 (M⁺).

EXAMPLE 52(3)

[0478] A mixture of2-(cis-4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(64.0 mg), methanol (5 mL), tetrahydrofuran (5 mL) and 1N-sodiumhydroxide solution (1 mL) was stirred for 2 hours at 60° C. Afterevaporation of the organic solvent, the aqueous layer was diluted withwater and extracted with ethyl acetate. The extract was washed with anaqueous saturated sodium bicarbonate solution, water and brine, driedover magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether to give2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamideas yellow powders (50.5 mg).

[0479] NMR (CDCl₃, δ): 1.70-1.95 (8H, br), 3.58 (1H, br), 3.93 (1H, br),4.51 (2H, d, J=7 Hz), 5.97 (2H, s), 6.43 (1H, br), 6.67 (1H, d, J=8 Hz),6.78-6.87 (3H, m), 8.14 (1H, dd, J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 9.03(1H, br)

[0480] Mass m/z: 412 (M⁺).

EXAMPLE 53

[0481]2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(2-pyrazinylmethyl)benzamide(129 mg) was obtained as yellow powders from2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (150 mg) and2-pyrazinylmethylamine (70.1 mg) in a manner similar to Example 51.

[0482] NMR (DMSO-d₆, δ): 1.13-1.40 (4H, br), 1.70-1.88 (2H, br),1.89-2.02 {2H, br), 3.40-3.60 (2H, br), 4.53-4.68 (3H, br), 6.92 (1H, d,J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.55 (1H, d, J=4 Hz), 8.58-8.70 (2H,m), 8.98 (1H, d, J=8 Hz), 9.50 (1H, br).

EXAMPLE 54

[0483]2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(3,4,5-trimethoxybenzyl)benzamide(106 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (80.0 mg) and3,4,5-trimethoxybenzylamine (67.6 mg) in a manner similar to Example 51.

[0484] NMR (DMSO-d₆, δ): 1.46-1.75 (8H, br), 3.63 (3H, s), 3.61-3.72(2H, br), 3.76 (6H, s), 4.39 (2H, d, J=7 Hz), 4.54 (1H, d, J=4 Hz), 6.67(2H, s), 6.89 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.62 (1H, d,J=4 Hz), 9.22 (1H, br), 9.33 (1H, br).

[0485] Preparation 55

[0486] To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) indichloromethane (4 mL) were added thionyl chloride (0.17 mL) anddimethylformamide (0.05 mL), and the mixture was heated for 36 hoursunder reflux. After evaporation of the solvent, the residue wasdissolved in dichloromethane (4 mL). To this solution were addedbenzylamine (0.19 mL) and triethylamine (0.47 mL), and the mixture wasstirred for 30 minutes at 0° C. After evaporation of the solvent, theresidue was dissolved in ethyl acetate and washed successively withdiluted hydrochloric acid, an aqueous sodium bicarbonate solution andbrine. The organic layer was dried over sodium sulfate and evaporated tnvacuo. The resulting residue was triturated with diisopropyl ether togive N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid substance.

[0487] NMR (DMSO-d₆, δ): 4.50 (2H, d, J=6 Hz), 7.22-7.40 (5H, m), 7.64(1H, t, J=8 Hz), 8.38-8.47 (2H, m), 9.19 (1H, t, J=6 Hz).

EXAMPLE 55

[0488] N-Benzyl-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide (54.5 mg) was obtained fromN-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and 2-amino-1,3-propanediol(59.8 mg) in a manner similar to Example 1(1). mp: 171-173° C.

[0489] NMR (DMSO-d₆, δ): 3.45-3.5 (5H, m), 4.43 (2H, d, J=7 Hz), 4.91(2H, t, J=6 Hz), 6.92 (1H, d, J=8 Hz), 7.2-7.4 (5H, m), 8.13 (1H, dd,J=2, 8 Hz), 8.62 (1H, d, J=2 Hz), 9.28 (1H, d, J=7 Hz), 9.36 (1H, t, J=6Hz).

EXAMPLE 56

[0490] N-Benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (346mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (300 mg) andtrans-2-aminocyclohexanol (186 mg) in a manner similar to Example 1 (1).

[0491] mp: 233-234° C.

[0492] NMR (DMSO-d₆, δ): 1.17-1.46 (4H, m), 1.72-1.87 (2H, m), 1.92-2.04(2H, m), 3.4-3.6 (2H, m), 4.42 (2H, d, J=7 Hz), 4.62 (1H, d, J=6 Hz),6.90 (1H, d, J=8 Hz), 7.22-7.39 (5H, m), 8.13 (1H, dd, J=2.8 Hz), 8.63(1H, d, J=2 Hz), 9.10 (1H, d, J=7 Hz), 9.41 (1H, t, J=6 Hz).

EXAMPLE 57

[0493] N-Benzyl-2-(morpholinoamino)-5-nitrobenzamide (41 mg) wasobtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and4-aminomorpholine (40.9 mg) in a manner similar to Example 1 (1).

[0494] NMR (DMSO-d₆, δ): 2.63-2.84 (4H, m), 3.22-3.78 (4H, m), 4.42 (2H,d, J=6 Hz), 7.2-7.4 (5H, m), 8.17 (1H, dd, J=2, 8 Hz), 8.63 (1H, d, J=2Hz), 9.41 (1H, t, J=6 Hz), 9.55 (1H, s)

[0495] Mass m/z: 355 (M⁺−1).

EXAMPLE 58

[0496] N-Benzyl-5-nitro-2-(piperidinoamino)benzamide (65 mg) wasobtained from N-benzyl-2-fluoro-5-nitrobenzamide (111 mg) and4-aminopiperidine (44.6 mg) in a manner similar to Example 1(1).

[0497] NMR (DMSO-d₆, δ): 1.55-1.7 (6H, m), 2.4-3.0 (4H, m), 4.43 (2H, d,J=6 Hz), 7.2-7.4 (5H, m), 8.16 (1H, dd, J=2, 8 Hz), 8.63 (1H, d, J=2Hz), 9.42 (1H, t, J=6 Hz), 9.56 (1H, s)

[0498] Mass m/z: 353 (M⁺−1).

EXAMPLE 59

[0499] N-Benzyl-5-nitro-2-(2-thiazolylamino)benzamide (22.7 mg) wasobtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and2-aminothiazole (43.8 mg) in a manner similar to Example 1(1).

[0500] NMR (DMSO-d₆, δ): 4.54 (2H, d, J=6 Hz), 7.2-7.5 (6H, m), 7.48(1H, m), 8.41 (1H, m), 8.73 (1H, d, J=9 Hz), 8.79 (1H, d, J=2 Hz), 9.79(1H, t, J=6 Hz)

[0501] Mass m/z: 353 (M⁺−1).

EXAMPLE 60

[0502] N-Benzyl-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide(215 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (181 mg)and trans-2-aminocyclopentanol (100 mg) in a manner similar to Example1(1).

[0503] NMR (CDCl₃, δ): 1.54-1.96 (5H, m), 2.00-2.12 (1H, m), 2.25-2.37(1H, m), 3.78 (1H, m), 4.16 (1H, m), 4.58 (2H, d, J=7 Hz), 6.60 (1H,br), 6.86 (1H, d, J=8 Hz), 7.28-7.40 (5H, m), 8.15 (1H, dd, J=4, 8 Hz),8.32 (1H, d, J=4 Hz), 8.85 (1H, br)

[0504] Mass m/z: 354 (M⁺).

[0505] Preparation 61 (1)

[0506] To a solution of 1,3-cyclopentanediol (500 mg) in pyridine (10mL) was added benzoyl chloride (688 mg), and the mixture was stirred for18 hours at ambient temperature. After evaporation of the solvent, theresidue was partitioned between ethyl acetate and water. The separatedorganic layer was washed with 1N-hydrochloric acid, water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by a silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (3:1 to 1:1) to give 3-hydroxycyclopentylbenzoate as a colorless oil (630 mg).

[0507] NMR (CDCl₃, δ): 1.63-1.78 (1H, m), 1.80-2.00 (1H, br), 2.04-2.20(3H, m), 2.22-2.40 (1H, m), 4.40 and 4.56 (1H, m), 5.40 and 5.54 (1H,br), 7.42 (2H, m), 7.53 (1H, m), 8.00 (2H, d, J=8 Hz).

[0508] Preparation 61(2)

[0509] To a solution of 3-hydroxycyclopentyl benzoate (630 mg) inanhydrous tetrahydrofuran (15 mL) were added diphenylphosphoryl azide(925 mg), diethyl azodicarboxylate (585 mg) and triphenylphosphine (881mg). After stirring for 2 hours at ambient temperature, the mixture waspartitioned between ethyl acetate and water. The separated organic layerwas washed with brine, dried over magnesium sulfate and evaporated invacuo. The residue was purified by a silica gel column chromatographyeluting with a mixture of hexane and ethyl acetate (10:1) to give3-azidocyclopentyl benzoate as pale yellow oil (531 mg).

[0510] NMR (CDCl₃, δ): 1.74-2.46 (6H, br), 4.12-4.28 (1H, br), 5.28-5.54(1H, br), 7.37-7.50 (2H, br), 7.51-7.62 (1H, br), 7.94-8.10 (2H, m).

[0511] Preparation 61(3)

[0512] A mixture of 3-azidocyclopentyl benzoate (411 mg) and 10%palladium on activated carbon (41.1 mg) in methanol (15 mL) was stirredunder hydrogen atmosphere (4 atrn) for 2 hours at ambient temperature.After removal of the catalyst, the filtrate was evaporated in vacuo togive 3-aminocyclopentyl benzoate as a pale yellow oil (354 mg).

[0513] NMR (CDCl₃, δ): 1.40-2.20 (5H, br), 2.41 (1H, m), 3.43 (1H, m),5.38 (1H, br), 7.38-7.65 (3H, br), 8.03 (2H, d, J=8 Hz).

EXAMPLE 61 (1)

[0514] 2-[3-(Benzoyloxy)cyclopentylamino]-N-benzyl-5-nitrobenzamide (158mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and3-aminocyclopentyl benzoate (112 mg) in a manner similar to Example 1(1).

[0515] NMR (CDCl₃, δ): 1.88-2.30 (5H, br), 2.57 (1H, m), 4.08 (1H, br),4.59 (2H, d, J=7 Hz), 5.51 (1H, br), 6.48 (1H, br), 6.68 (1H, d, J=8Hz), 7.20-7.48 (7H, m), 7.52 (1H, m), 8.10 (2H, d, J=8 Hz), 8.18 (1H,dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 9.20 (1H, br)

[0516] Mass m/z: 458 (M⁺).

EXAMPLE 61(2)

[0517] N-Benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide (129 mg)was obtained from2-(3-benzoyloxyccyclopentylamino)-N-benzyl-5-nitrobenzamide (189 mg) ina manner similar to Example 52(3).

[0518] NMR (CDCl₃, δ): 1.62 (1H, d, J=7 Hz), 1.74-1.98 (4H, m),2.09-2.36 (2H, m), 3.99 (1H, m), 4.47 (1H, br), 4.60 (2H, d, J=7 Hz),6.47 (1H, br), 6.65 (1H, d, J=8 Hz), 7.28-7.40 (5H, m), 8.16 (1H, dd,J=4, 8 Hz), 8.31 (1H, d, J=4 Hz), 9.05 (1H, br)

[0519] Mass m/z: 356 (M⁺).

[0520] Preparation 62

[0521] N-(3-Chloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (320 mg)was obtained as yellow oil from 2-fluoro-5-nitrobenzoic acid (300 mg)and 3-chloro-4-methoxybenzylamine hydrochloride (405 mg) in a mannersimilar to Preparation 1.

[0522] NMR (DMSO-d₆, δ): 3.90 (3H, s), 4.60 (2H, d, J=7 Hz), 6.90 (1H,d, J=8 Hz), 6.88-7.00 (1H, br), 7.20-7.40 (3H, m), 8.38 (1H m), 9.00(1H, m).

EXAMPLE 62

[0523]N-(3-Chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylamino]-5-nitrobenzamide(85.0 mg) was obtained fromN-(3-chloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (105 mg) and2-amino-1,3-propanediol (42.4 mg) in a manner similar to Example 1(1).

[0524] NMR (DMSO-d₆, δ): 3.54 (4H, br), 3.62 (1H, br), 3.83 (3H, s),4.36 (2H, d, J=7 Hz), 4.92 (2H, t, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.11(1H, d, J=8 Hz), 7.26 (1H, dd, J=4, 8 Hz), 7.38 (1H, d, J=4 Hz), 8.10(1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 9.30 (2H, br)

[0525] Mass m/z: 408 (M⁺).

EXAMPLE 63(1)

[0526]N-(3-Chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclo-hexylamino)-5-nitrobenzamide(200 mg) was obtained fromN-(3-chloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (210 mg) andtrans4-aminocyclohexanol (107 mg) in a manner similar to Example 1(1).

[0527] NMR (DMSO-d₆, δ): 1.30 (4H, br), 1.80 (2H, br), 1.95 (2H, br),3.50 (2H, br), 3.82 (3H, s), 4.35 (2H, d, J=7 Hz), 4.60 (1H, d, J=4 Hz),6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.25 (1H, dd, J=4, 8 Hz),7.40 (1H, d, J=4 Hz), 8.10 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz),9.04 (1H, d, J=8 Hz), 9.36 (1H, br)

[0528] Mass m/z: 432 (M⁺).

EXAMPLE 63(2)

[0529] 2-[cis-4-(Benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide (155 mg)was obtained from N-(3-chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(197 mg)in a manner similar to Example 52(2).

[0530] NMR (CDCl₃, δ): 1.80-2.20 (8H, br), 3.60 (1H, br), 3.91 (3H, s),4.54 (2H, d, J=7 Hz), 5.25 (1H, br), 6.53 (1H, br), 6.72 (1H, d, J=8Hz), 6.95 (1H, d, J=8 Hz), 7.25 (1H, m), 7.39-7.50 (3H, m), 7.60 (1H,m), 8.07 (2H, d, J=8 Hz), 8.18 (1H, dd, J=4, 8 Hz), 8.34 (1H, d, J=4Hz), 9.02 (1H, br).

EXAMPLE 63(3)

[0531]N-(3-Chloro-4-methoxybenzyl)-2-(cis-4-hydroxy-cyclohexylamino)-5-nitrobenzamide(85.0 mg) was obtained from2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide(155 mg) in a manner similar to Example 52(3).

[0532] NMR (DMSO-d₆, δ) 1.43-1.70 (8H, br), 3.66 (2H, br), 3.83 (3H, s),4.38 (2H, d, J=7 Hz), 4.54 (1H, d, J=4 Hz), 6.88 (1H, d, J=8 Hz), 7.12(1H, d, J=8 Hz), 7.28 (1H, dd, J=4, 8 Hz), 7.39 (1H, d, J=4 Hz), 8.11(1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.26 (1H, d, J=8 Hz), 9.36(1H, br)

[0533] Mass m/z: 432 (M⁺).

[0534] Preparation 64

[0535] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (14.2 g) wasobtained from 2-fluoro-5-nitrobenzoic acid (10.0 g) and3,4-dimethoxybenzylamine (9.30 g) in a manner similar to Preparation 55.

[0536] NMR (CDCl₃, δ): 3.89 (6H, s), 4.63 (2H, d, J=7 Hz), 6.84-6.93(4H, m), 7.30 (1H, m), 8.35 (1H, m), 9.03 (1H, m)

[0537] Mass m/z: 333 (M⁺).

EXAMPLE 64(1)

[0538](R)-N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nitrobenzamide(156 mg) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and(R)-2-amino-1-propanol (50.6 mg) in a manner similar to Example 1(1).

[0539] mp: 125-127° C.

[0540] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 3.46 (2H, br), 3.72 (3H,s), 3.74 (3H, s), 3.75 (1H, br), 4.36 (2H, d, J=7 Hz), 4.99 (1H, t, J=7Hz), 6.83-6.95 (4H, m), 8.09 (1H, dd, J=4, 8 Hz), 8.57 (1H, d, J=4 Hz),9.09 (1H, d, J=8 Hz), 9.28 (1H, br)

[0541] Mass m/z: 388 (M⁺).

EXAMPLE 64(2)

[0542] To a mixture of(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide(5.00 g), 4-dimethylaminopyridine (1.57 g, 12.8 mmol) and triethylamine(1.79 mL) in dichloromethane (150 mL) was added acetyl chloride (1.83mL), and the mixture was stirred for 5 hours at ambient temperature. Themixture was washed with 1N-hydrochloric acid, water, an aqueoussaturated sodium bicarbonate solution and brine. Then, the resultant wasdried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether. The obtained product wasrecrystallized from a mixture of ethyl acetate and hexane (1:1) to give(R)-2-(2-acetoxy-1-methylethylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamideas yellow crystals (5.10 g).

[0543] NMR (DMSO-d₆, δ): 1.22 (3H, d, J=7 Hz), 1.99 (3H, s), 3.73 (3H,s), 3.74 (3H, s), 4.00-4.12 (1H, br), 4.09 (2H, br), 4.37 (2H, d, J=7Hz), 6.82-6.98 (4H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz),9.06 (1H, d, J=8 Hz), 9.33 (1H, br)

[0544] Mass m/z: 430 (M⁺).

EXAMPLE 64(3)

[0545] To a solution of(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide(200 mg) in 1,2-dichloroethane (10 mL) were added trimethyloxoniumtetrafluoroborate (91.2 mg) and 2,6-di-tert-butyl-4-methylpyridine (158mg), and the mixture was heated for 3 hours under reflux. The mixturewas washed with 1N-hydrochloric acid, water, an aqueous saturated sodiumbicarbonate solution and brine. Then, the resultant was dried overmagnesium sulfate and evaporated in vacuo. The residue was purified by asilica gel column chromatography eluting with a mixture of hexane andethyl acetate (3:1 to 1:1). The obtained product was triturated withdiisopropyl ether to give(R)-N-(3,4-dimethoxybenzyl)-2-(2-methoxy-1-methylethylamino)-5-nitrobenzamideas yellow powders (145 mg).

[0546] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 3.29 (3H, s), 3.42 (2H,br), 3.73 (3H, s), 3.74 (3H, s), 3.88-4.00 (1H, br), 4.37 (2H, d, J=7Hz), 6.85-6.96 (4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz),9.09 (1H, d, J=8 Hz), 9.29 (1H, br)

[0547] Mass m/z: 402 (M⁺).

EXAMPLE 65

[0548](S)-N-(3,4-Dimethoxybenzyl)-2-[1-(hydroxymethyl)-propylamino]-5-nitrobenzamide(130 mg) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and(S)-2-amino-1-butanol (60.0 mg) in a manner similar to Example 1(1).

[0549] mp: 168-169° C.

[0550] NMR (DMSO-d₆, δ): 0.90 (3H, t, J=7 Hz), 1.40-1.78 (2H, m), 3.48(2H, br), 3.57 (1H, br), 3.72 (3H, s), 3.74 (3H, s), 4.38 (2H, br), 4.92(1H, t, J=7 Hz), 6.83-6.95 (4H, m), 8.08 (1H, dd, J=4, 8 Hz), 8.57 (1H,d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.29 (1H, br)

[0551] Mass m/z: 402 (M⁺).

EXAMPLE 66

[0552]N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-5-nitrobenzamide(156 mg) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and2-amino-2-methyl-1-propanol (120 mg) in a manner similar to Example 1(1).

[0553] mp: 161-162° C.

[0554] NMR (DMSO-d₆, δ): 1.33 (6H, s), 3.43 (2H, d, J=7 Hz), 3.73 (3H,s), 3.74 (3H, s), 4.36 (2H, d, J=7 Hz), S.19 (1H, t, J=7 Hz), 6.80-6.96(3H, m), 7.04 (1H, d, J=8 Hz), 8.07 (1H, dd, J=4, 8 Hz), 8.51 (1H, d,J=4 Hz), 9.27 (2H, br)

[0555] Mass m/z: 402 (M⁺).

EXAMPLE 67

[0556]N-(3,4-Dimethoxybenzyl)-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide(6.18 g) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (6.00 g) andtrans-2-aminocyclopentanol (3.63 g) in a manner similar to Example 1(1).

[0557] mp: 154-155° C.

[0558] NMR (DMSO-d₆, δ): 1.60-1.96 (5H, m), 2.00-2.14 (1H, m), 2.27-2.40(1H, m), 3.78 (1H, br), 3.89 (3H, s), 3.90 (3H, s), 4.16 (1H, br), 4.53(2H, d, J=7 Hz), 6.50 (1H, br), 6.88 (4H, br), 8.16 (1H, dd, J=4, 8 Hz),8.31 (1H, d, J=4 Hz), 8.85 (1H, br)

[0559] Mass m/z: 414 (M⁺).

EXAMPLE 68

[0560](S)-N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nitrobenzamide(188 mg) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and(S)-2-amino-1-propanol (89.9 mg) in a manner similar to Example 1(1).

[0561] mp: 131-132° C.

[0562] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 3.46 (2H, br), 3.72 (3H,s), 3.74 (3H, s), 3.75 (1H, br), 4.36 (2H, d, J=7 Hz), 4.99 (1H, t, J=7Hz), 6.83-6.95 (4H, m), 8.09 (1H, dd, J=4, 8 Hz), 8.57 (1H, d, J=4 Hz),9.09 (1H, d, J=8 Hz), 9.28 (1H, br)

[0563] Mass m/z: 388 (M⁺).

EXAMPLE 69

[0564]N-(3,4-Dimethoxybenzyl)-5-nitro-2-[2-(2,2,2-trifluoroethyl)hydrazino]benzamide(27 mg) was obtained as a yellow solid substance fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and2,2,2-trifluoroethylhydrazine (116 mg) in a manner similar to Example1(1).

[0565] mp: 140-142° C.

[0566] NMR (DMSO-d₆, δ); 3.47-3.65 (2H, m), 3.73 (3H, s), 3.74 (3H, s),4.38 (2H, d, J=5.5 Hz), 5.81 (1H, t, J=4 Hz), 6.85 (1H, d, J=8.5 Hz),6.91 (1H, d, J=8.5 Hz), 6.96 (1H, s), 7.39 (1H, d, J=8.5 Hz), 8.18 (1H,dd, J=8.5, 1.5 Hz), 8.57 (1H, d, J=1.5 Hz), 9.31 (1H, t, J=5.5 Hz), 9.84(1H, s)

[0567] Mass m/z: 427 (M⁺−1).

EXAMPLE 70

[0568] N-(3,4-Dimethoxylbenzyl)-2-{[(1R,2S)-cis-2,3-dihydro-2-hydroxy-1H-inden-1-yl]amino}-5-nitrobenzamide (192mg) was obtained as yellow powders fromN-(3,4-dimethoxylbenzyl)-2-fluoro-5-nitrobenzamide (153 mg) and(1R,2S)-cis-1-amino-2-indanol (137 mg) in a manner similar to Example1(1).

[0569] mp. 248-250° C.

[0570] NMR (DMSO-d₆, δ); 2.86 (1H, d, J=16 Hz), 3.11 (1H, dd, J=16, 5Hz), 3.71 (3H, s), 3.72 (3H, s), 4.30-4.44 (2H, m), 4.58 (1H, m), 5.18(1H, m), 5.37 (1H, d, J=5 Hz), 6.80-6.97 (3H, m), 7.07-7.34 (5H, m),8.17 (1H, dd, J=10, 2 Hz), 8.63 (1H, d, J=2 Hz), 9.30 (1H, t, J=6 Hz),9.55 (1H, d, J=8 Hz)

[0571] Mass m/z: 462 (M⁺).

EXAMPLE 71

[0572] N-(3,4-Dimethoxylbenzyl)-2-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino-5-nitrobenzamide (167 mg) wasobtained as yellow powders from2-fluoro-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (145 mg) and(1S,2R)-(+)-Norephedrine (97 mg) in a manner similar to Example 1 (1).

[0573] m.p. 248-250° C.

[0574] NMR (DMSO-d₆, δ); 2.86 (1H, d, J=16 Hz), 3.11 (1H, dd, J=16, 5Hz), 3.71 (3H, s), 3.72 (3H, s), 4.30-4.44 (2H, m), 4.58 (1H, m), 5.18(1H, m), 5.37 (1H, d, J=5 Hz), 6.80-6.97 (3H, m), 7.07-7.34 (5H, m),8.17 (1H, dd, J=10, 2 Hz), 8.63 (1H, d, J=2 Hz), 9.30 (1H, t, J=6 Hz),9.55 (1H, d, J=8 Hz)

[0575] Mass m/z: 462 (M⁺).

EXAMPLE 72

[0576] 2-[(1S,2R)-1-(Carbamoyl)-2-hydroxypropylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(151 mg) was obtained as yellow crystals fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) andL-threoninamide hydrocloride (139 mg) in a manner similar to Example 1(1).

[0577] NMR (DMSO-d₆, δ): 1.13 (3H, d, J=6 Hz), 3.73 (3H, s), 3.75 (3H,s), 3.91(1H, m), 4.06 (1H, m), 4.50 (2H, m), 5.23 (1H, d, J=4 Hz), 6.69(1H, d, J=9 Hz), 6.81 (1H, brd, J=8 Hz), 6.92 (1H, d, J=8 Hz), 6.98 (1H,br), 7.26 (1H, s), 7.44 (1H, s), 8.14 (1H, dd, J=3, 9 Hz), 8.59 (1H, d,J=3 Hz), 9.28 (1H, t, J=5 Hz), 9.38 (1H, d, J=5 Hz)

[0578] Mass (ESI−): 431 (M−H).

EXAMPLE 73(1)

[0579]2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(12.3 g) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (10.0 g) andtrans-1,4-diaminocyclohexane (10.2 g) in a manner similar to Example1(1).

[0580] NMR (DMSO-d₆, δ): 1.10-1.38 (4H, br), 1.72-1.82 (2H, br),1.94-2.05 (2H, br), 2.60 (1H, br), 3.46 (1H, br), 3.73 (3H, s), 3.74(3H, s), 4.36 (2H, d, J=7 Hz), 6.83-6.95 (4H, m), 8.10 (1H, dd, J=4, 8Hz), 8.59 (1H, d, J=4 Hz), 9.01 (1H, d, J=8 Hz), 9.31 (1H, br)

[0581] Mass m/z: 429 (M⁺).

EXAMPLE 73(2)

[0582] To a solution of2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5nitrobenzamide(10 g) in dimethylformamide (60 mL) was added ethyl formate (200 mL),and the mixture was heated for 8 hours under reflux. The mixture waspartitioned between ethyl acetate and water. The separated organic layerwas washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by a silica gel columnchromatography eluting with a mixture of chloroform and methanol (20:1).The obtained product was recrystallized from ethanol to giveN-(3,4-dimethoxybenzyl)-2-[(trans4-formamidocyclohexyl)amino]-5-nitrobenzamideas yellow crystals (7.21 g)

[0583] NMR (DMSO-d₆, δ): 1.25-1.55 (4H, br), 1.79-1.92 (2H, br),1.95-2.10 (2H, br), 3.47-3.59 (1H, br), 3.60-3.72 (1H, br), 3.73 (3H,s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96 (4H, m), 7.95 (1H, s),8.04 (1H, br), 8.08 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.01 (1H,d, J=8 Hz), 9.32 (1H, br)

[0584] Mass m/z: 455 (M⁺).

EXAMPLE 73(3)

[0585] Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) wereadded to a solution of2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(134 mg) in chloroform (2 mL). The mixture was stirred for an hour atambient temperature.

[0586] Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) wereadded to the reaction mixture. After stirring for an hour at ambienttemperature, the mixture was concentrated in vacuo. The residue waspartitioned between ethyl acetate and 3.6% hydrochloric acid. Theseparated organic layer was washed with an saturated aqueous sodiumbicarbonate solution and brine, dried over magnesium sulfate andconcentrated in vacuo. The residual crystals were suspended in hotethanol and cooled with stirring. The resultant was collected byfiltration and washed with ethanol to giveN-(3,4-dimethoxybenzyl)-2-trans4-(methanesulfonylamino)cyclohexylamino]-5-nitrobenzamide(142 mg) as yellow crystals.

[0587] NMR (DMSO-d₆, δ): 1.25-1.50 (4H, m), 1.88-2.05 (4H, m), 2.92 (3H,s), 3.18 (1H, m), 3.34-3.54 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 4.37(2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.88-6.97 (3H, m), 7.09 (1H,d, J=7 Hz), 8.10 (1H, dd, J=2, 8 Hz), 8.60 (1H, d, J=2 Hz), 9.00 (1H,dd, J=7 Hz), 9.32 (1H, t, J=6 Hz)

[0588] Mass (ESI−) 505 (M−H).

EXAMPLE 73(4)

[0589]2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(110 mg) was obtained as yellow powders from2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(100 mg) and acetic acid (15.4 mg) in a manner similar to Example24(3).

[0590] NMR (DMSO-d₆, δ): 1.22-1.45 (4H, br), 1.79 (3H, s), 1.75-1.90(2H, br), 1.96-2.09 (2H, br), 3.44-3.63 (2H, br), 3.73 (3H, s), 3.74(3H, s), 4.36 (2H, d, J=7 Hz), 6.82-6.95 (4H, m), 7.78 (1H, d, J=8 Hz),8.10 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.02 (1H, d, J=8 Hz),9.32 (1H, br)

[0591] Mass m/z: 469(M⁺).

EXAMPLE 73(5)

[0592] To a solution of2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(100 mg) in dichloromethane (3 mL) was added propyl isocyanate (21.8mg), and the mixture was stirred for 2 hours at ambient temperature.After evaporation of the solvent, the residue was triturated with ethylacetate to giveN-(3,4-dimethoxybenzyl)-5-nitro-2-[trans-4-(3-propylureido)cyclohexylamino]benzamideas yellow powders (118 mg).

[0593] NMR (DMSO-d₆, δ): 0.82 (3H, t, J=7 Hz), 1.20-1.45 (6H, m),1.79-1.90 (2H, br), 1.96-2.10 (2H, br), 2.92 (2H, q, J=7 Hz), 3.40 (1H,br), 3.51 (1H, br), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz),5.70 (2H, br), 6.82-6.96 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.59 (1H, d,J=4 Hz), 9.02 (1H, d, J=8 Hz), 9.31 (1H, br)

[0594] Mass m/z: 512 (M⁺).

EXAMPLE 73(6)

[0595]N-(3,4-Dimethoxybenzyl)-5-nitro-2-[trans4-(3-phenylureido)cyclohexylamino]benzamide(158 mg) was obtained as yellow powders from2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-S-nitrobenzamide(150 mg) and phenyl isocyanate (45.9 mg) in a manner similar to Example73(5).

[0596] NMR (DMSO-d₆, δ): 1.28-1.47 (4H, br), 1.87-1.96 (2H, br),1.96-2.10 (2H, br), 3.45-3.63 (2H, br), 3.73 (3H, s), 3.75 (3H, s), 4.37(2H, d, J=7 Hz), 6.12 (1H, d, J=8 Hz), 6.83-6.98 (5H, m), 7.21 (2H, m),7.37 (2H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.31 (1H, s), 8.61 (1H,d, J=4 Hz), 9.05 (1H, d, J=8 Hz), 9.33 (1H, br)

[0597] Mass m/z: 546(M⁺).

EXAMPLE 73(7)

[0598] To a mixture of2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(300 mg) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (203mg) in ethanol (20 mL) was added mercury(II) oxide (152 mg). The mixturewas stirred for 2 hours at ambient temperature. The resultantprecipitates were removed by filtration and the filtrate was evaporatedin vacuo. The residue was purified by a silica gel column chromatographyeluting with 2% methanol in chloroform. The obtained product wastriturated with diisopropyl ether to give2-{trans4-[2,3-bis(tert-butoxycarbonyl)guanidino]cyclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellowpowders (432 mg).

[0599] NMR (CDCl₃, δ): 1.25-1.45 (4H, br), 1.50 (9H, s), 1.52 (9H, s),1.95-2.10 (4H, br), 3.28-3.40 (1H, br), 3.89 (3H, s), 3.91 (3H, s),3.85-4.00 (1H, br), 4.54 (2H, d, J=7 Hz), 6.58 (1H, d, J=8 Hz),6.85-6.98 (4H, m), 8.14 (1H, dd, J=4, 8 Hz), 8.28 (1H, d, J=8 Hz), 8.42(1H, d, J=4 Hz), 8.89 (1H, d, J=8 Hz)

[0600] Mass m/z: 671 (M⁺).

EXAMPLE 73(8)

[0601] To a solution of2-{trans4-[2,3-bis(tert-butoxycarbonyl)guanidino]cyclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(200 mg) in ethyl acetate (4 mL) was added 4N-hydrochloric acid in ethylacetate (8 mL). The mixture was stirred for 15 hours at ambienttemperature. After evaporation of the solvent, the residue wastriturated with ethyl acetate to giveN-(3,4-dimethoxybenzyl)-2-(trans4-guanidinocyclohexylamino)-5-nitrobenzamidehydrochloride as yellow powders (145 mg).

[0602] NMR (DMSO-d₆, δ): 1.22-1.53 (4H, br), 1.86-1.97 (2H, br),2.00-2.11 (2H, br), 3.22-3.62 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 4.37(2H, d, J=7 Hz), 6.84-6.96 (4H, m), 7.72 (1H, d, J=8 Hz), 8.12 (1H, dd,J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.02 (1H, d, J=8 Hz), 9.35 (1H, br)

[0603] Mass m/z: 471 (M⁺).

EXAMPLE 73(9)

[0604] A mixture of 2-fluoro-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(200 mg) and trans-4-formamidocyclohexylamine (170 mg) in pyridine (2mL) was stirred for 4 hours at 50° C. The mixture was partitionedbetween ethyl acetate and water. The separated organic layer was washedwith 1N HCl and brine, dried over magnesium sulfate and evaporated invacuo. The residue was purified by a silica gel column chromatographyeluting with 5% methanol in chloroform. The obtained product wasrecrystallized from acetone (2 mL) to give1-(3,4-dimethoxybenzyl)-2-[(trans4-formamidocyclohexyl)amino]-5-nitrobenzamideas yellow crystals (164 mg).

[0605] NMR (DMSO-d₆, δ): 1.25-1.55 (4H, br), 1.79-1.92 (2H, br),1.95-2.10 (2H, br), 3.47-3.59 (1H, br), 3.60-3.72 (1H, br), 3.73 (3H,s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96 (4H, m), 7.95 (1H, s),8.04 (1H, br), 8.08 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.01 (1H,d, J=8 Hz), 9.32 (1H, br)

[0606] Mass m/z: 455 (M⁺).

EXAMPLE 74(1)

[0607]2-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(1.06 mg) was obtained as yellow powders fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (1.00 g) andtert-butyl 4-amino-1-piperidinecarboxylate (899 mg) in a manner similarto Example 1 (1).

[0608] NMR (CDCl₃, δ): 1.48 (9H, s), 1.52-1.65 (2H, br), 1.95-2.10 (2H,br), 3.03-3.17 (2H, br), 3.64 (1H, br), 3.89 (3H, s), 3.90 (3H, s),3.94-4.06 (2H, br), 4.52 (2H, d, J=7 Hz), 6.49 (1H, br), 6.69 (1H, d,J=8 Hz), 6.84-6.95 (3H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.33 (1H, d, J=4Hz), 8.98 (1H, br)

[0609] Mass m/z: 513 (M⁺).

EXAMPLE 74(2)

[0610] N-(3,4-Dimethoxybenzyl)-5-nitro-2-(4-piperidinylamino)benzamide(713 mg) was obtained as yellow powders from2-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(950 mg) in a manner similar to Example 24(2).

[0611] NMR (DMSO-d₆, δ): 1.20-1.40 (2H, br), 1.83-1.96 (2H, br),2.55-2.65 (2H, br), 2.85-2.98 (2H, br), 3.56-3.68 (1H, br), 3.73 (3H,s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96 (4H, m), 8.11 (1H, dd,J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.10 (1H, d, J=8 Hz), 9.32 (1H, br)

[0612] Mass m/z: 415 (M⁺).

EXAMPLE 74(3)

[0613] 2-[1-[1,3-Bis (tert-butoxycarbonyl)amidino]piperidin-4-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(299 mg) was obtained as yellow powders fromN-(3,4-dimethoxybenzyl)-5-nitro-2-(4-piperidinylamino)benzamide (200 mg)in a manner similar to Example 73(7).

[0614] NMR (CDCl₃, δ): 1.49 (9H, s), 1.51 (9H, s), 1.70-1.85 (2H, br),2.05-2.18 (2H, br), 3.19-3.34 (2H, br), 3.67-3.78 (1H, br), 3.89 (3H,s), 3.90 (3H, s), 3.95-4.15 (2H, br), 4.53 (2H, d, J=7 Hz), 6.59 (1H,br), 6.69 (1H, d, J=8 Hz), 6.84-6.91 (3H, m), 8.16 (1H, dd, J=4, 8 Hz),8.34 (1H, d, J=4 Hz), 9.01 (1H, d, J=8 Hz)

[0615] Mass m/z: 655 (M⁺).

EXAMPLE 74(4)

[0616]2-(1-Amidinopiperidin-4-ylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamidehydrochloride (150 mg) was obtained as yellow powders from2-[1-[1,3-bis(tert-butoxycarbonyl)amidino]piperidin-4-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(200 mg) in a manner similar to Example 73(8).

[0617] NMR (DMSO-d₆, δ): 1.40-1.58 (2H, br), 2.00-2.11 (2H, br),3.17-3.30 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 3.77-3.97 (3H, br), 4.37(2H, d, J=7 Hz), 6.82-7.04 (4H, m), 7.52 (4H, br), 8.14 (1H, dd, J=4, 8Hz), 8.63 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.38 (1H, br)

[0618] Mass m/z: 457 (M⁺).

EXAMPLE 75(1)

[0619]N-(3,4-Dimethoxybenzyl)-2(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(11.8 g) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (10.0 g) andtrans-4-aminocyclohexanol (6.89 g) in a manner similar to Example 1(1).

[0620] NMR (DMSO-d₆, δ): 1.23-1.41 (4H, m), 1.78-1.88 (2H, br),1.91-2.01 (2H, br), 3.50 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H,d, J=7 Hz), 4.62 (1H, d, J=4 Hz), 6.82-6.96 (4H, m), 8.11 (1H, m), 8.60(1H, m), 9.04 (1H, br), 9.32 (1H, br)

[0621] Mass m/z: 428 (M⁺).

EXAMPLE 75(2)

[0622]2-cis-4-(Benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(9.00 g) was obtained fromN-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(10.0 g) in a manner similar to Example 52(2).

[0623] NMR (CDCl₃, δ): 1.78-2.15 (8H, br), 3.61 (1H, br), 3.88 (3H, s),3.89 (3H, s), 4.56 (2H, d, J=7 Hz), 5.26 (1H, br), 6.48 (1H, br), 6.71(1H, d, J=8 Hz), 6.85-6.93 (3H, m), 7.42-7.50 (2H, m), 7.58 (1H, m),8.06 (2H, d, J=8 Hz), 8.18 (1H, dd, J=4, 8 Hz), 8.33 (1H, d, J=4 Hz),9.05 (1H, br)

[0624] Mass m/z: 532 (M⁺).

EXAMPLE 75(3)

[0625]N-(3,4-Dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(4.56 g) was obtained from 2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (9.00 g) andin a manner similar to Example 52(3).

[0626] NMR (DMSO-d₆, δ): 1.45-1.72 (8H, br), 3.66 (2H, br), 3.73 (3H,s), 3.75 (3H, s), 4.38 (2H, d, J=7 Hz), 4.55 (1H, d, J=4 Hz), 6.83-6.97(4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.26 (1H, br),9.32 (1H, br)

[0627] Mass m/z: 428 (M⁺).

EXAMPLE 75(4)

[0628] To a suspension ofN-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(1.0 g) in dichloromethane (20 mL) were added triethylamine (0.49 mL)and 4-dimethylaminopyridine (284 mg), and then acetyl chloride (0.20 mL)at 20° C. The reaction mixture was stirred for 2 hours at 20° C. andthen, acetyl chloride (0.05 mL) was added. After stirring for an hour at20° C., the reaction mixture was partitioned between chloroform and1N-hydrochloric acid. The separated organic layer was washed with waterand brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by a silica gel column chromatography eluting witha mixture of ethyl acetate and hexane (1:2). The residual solid wasrecrystallized from ethyl acetate to give2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(429 mg) as yellow crystals.

[0629] mp 147-148° C.

[0630] NMR (DMSO-d₆, δ); 1.55-1.90 (8H, br), 2.03 (3H, s), 3.73 (3H, s),3.74 (1H, m), 3.75 (3H, s), 4.39 (2H, d, J=8 Hz), 4.82 (1H, m), 6.85(1H, dd, J=2, 8 Hz), 6.92 (1H, d, J=8 Hz), 6.93 (1H, d, J=10 Hz), 6.97(1H, d, J=2 Hz), 8.12 (1H, dd, J=3, 10 Hz), 8.63 (1H, d, J=3 Hz), 9.26(1H, d, J=10 Hz), 9.36 (1H, t, J=6 Hz).

EXAMPLE 76(1)

[0631]N-(3,4-Dimethoxylbenzyl)-2-[(R)-1-methoxycarbonyl-3-(methylthio)propylamino]-5-nitrobenzamide(245 mg) was obtained from2-fluoro-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (210 mg) and(R)-methionine methyl ester (205 mg) in a manner similar to Example1(1).

[0632] NMR (DMSO-d₆, δ): 2.00-2.22 (2H, m), 2.03 (3H, s), 2.44-2.60 (2H,m), 3.70 (3H, s), 3.73 (3H, s), 3.75 (3H, s), 4.40 (2H, d, J=5 Hz), 4.61(1H, dt, J=8, 6 Hz), 6.79-7.00 (4H, m), 8.15 (1H, dd, J=9, 3 Hz), 8.63(1H, d, J=3 Hz), 9.32-9.43 (2H, m)

[0633] Mass m/z: 476 (M⁺).

EXAMPLE 76(2)

[0634] To a solution ofN-(3,4-dimethoxylbenzyl)-2-[(R)-1-methoxycarbonyl-3-(methylthio)propylamino]-5-nitrobenzamide (175 mg) in anhydrous tetrahydrofuran (3 mL) were addedlithium chloride (31 mg), and then sodium borohydride (28 mg) in ethanol(3 mL) at ambient temperature. The mixture was stirred for one day.After evaporation of the solvent, the residue was partitioned betweenethyl acetate and 10% citric acid aqueous solution. The separatedorganic layer was washed with water and brine and dried over magnesiumsulfate. The residual solid was recrystallized from ethyl acetate-hexaneto giveN-(3,4-dimethoxylbenzyl)-2-[(R)-1-hydroxymethyl-3-(methylthio)propylamino]-5-nitrobenzamide(122 mg).

[0635] m.p. 150-152° C.

[0636] NMR (DMSO-d₆, δ): 1.73 (1H, m), 1.92 (1H, m), 2.03 (3H, s),2.40-2.62 (2H, m), 3.50 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 3.78 (1H,m), 4.35 (1H, dd, J=15, 6 Hz), 4.40 (1H, dd, J=15, 6 Hz), 4.99 (1H, t,J=5 Hz), 6.80-6.99 (4H, m), 8.12 (1H, dd, J=9, 3 Hz), 8.58 (1H, d, J=3Hz), 8.58 (1H, d, J=3 Hz), 9.10 (1H, d, J=8 Hz), 9.30 (1H, dd, J=6, 6Hz)

[0637] Mass m/z: 448 (M⁺).

[0638] Preparation 77(1)

[0639] cis-4-(N-tert-Butoxycarbonylamino)cyclohexylazide (266 mg) wasobtained as an oil from trans4-(N-tert-butoxycarbonylamino)cyclohexanol(200 mg) in a manner similar to Preparation 61(2).

[0640] NMR (CDCl₃, δ): 1.44 (9H, s), 1.4-1.85 (8H, m), 3.51 (1H, br),3.71 (1H, br), 4.48 (1H, br).

[0641] Preparation 77(2)

[0642] cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamine (77 mg) wasobtained as an oil fromcis-4-(N-tert-butoxycarbonylamino)cyclohexylazide (252 mg) in a mannersimilar to Preparation 61(3).

[0643] NMR (CDCl₃, δ): 1.44 (9H, s), 1.5-1.8 (4H, m), 1.8-2.2 (4H, m),2.91 (1H, br), 3.65 (1H, br), 4.66 (1H, br)

[0644] Mass (ESI+) 215(M+H).

EXAMPLE 77(1)

[0645]2-[cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(282 mg) was obtained as amorphous powders fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) andcis-4-(N-tert-butoxycarbonylamino)cyclohexylamine (256 mg) in a mannersimilar to Example 1(1).

[0646] NMR (CDCl₃, δ): 1.45 (9H, s), 1.51-1.70 (2H, m), 1.75-1.94 (6H,m), 3.55-3.80 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.54 (2H, d, J=5 Hz),4.59 (1H, m), 6.49 (1H, m), 6.66 (1H, d, J=9 Hz), 6.82-6.95 (3H, m),8.15 (1H, d, J=9 Hz), 8.33 (1H, d, J=2 Hz), 9.17 (1H, d, J=7 Hz)

[0647] Mass (ESI−): 527(M−H).

EXAMPLE 77(2)

[0648] 4N-Hydrogen chloride solution in ethyl acetate (2 mL) was addedto a solution of2-[cis-4-(N-tert-butoxycarbonylamino)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(270 mg) in ethyl acetate (1 mL). The mixture was stirred for 2 hours atambient temperature. The reaction mixture was concentrated in vacuo. Tothe residue were added an aqueous saturated sodium bicarbonate solutionand ethyl acetate. The appeared precipitates were collected byfiltration and washed with ethyl acetate and water successively to give2-(cis-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(77 mg) as yellow powders. The filtrate was separated, and the aqueouslayer was extracted with chloroform. The combined organic layer wasdried over magnesium sulfate and concentrated in vacuo to give a secondcrop (137.8 mg).

[0649] NMR (DMSO-d₆, δ): 1.50-1.90 (8H, m), 3.16 (1H, m), 3.73 (3H, s),3.75 (3H, s), 3.80 (1H, m), 4.40 (2H, d, J=5 Hz), 6.83-6.99 (4H, m),8.14 (1H, dd, J=2, 9 Hz), 8.13 (1H, dd, J=2, 9 Hz), 8.66 (1H, d, J=3Hz), 9.35-9.44 (2H, m)

[0650] Mass: (ESI+) 429(M+H), (ESI−) 427(M−H).

EXAMPLE 77(3)

[0651]2-(cis-4-Formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(129mg) was obtained as yellow crystals from2-(cis-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(180 mg) in a manner similar to Example73(2).

[0652] NMR (DMSO-d₆, δ): 1.42-1.60 (2H, m), 1.60-1.83 (6H, m), 3.65-3.78(1H, m), 3.73 (3H, s), 3.85 (1H, m), 4.39 (2H, d, J=6 Hz), 6.82-6.98(4H, m), 7.95 and 8.03 (1H, s), 8.12 (1H, dd, J=2, 9 Hz), 8.20 (1H, d,J=7 Hz), 8.63 (1H, d, J=2 Hz), 9.27-9.41 (2H, m)

[0653] Mass: (ESI+) 457(M+H), (ESI−) 455(M−H).

[0654] Preparation 78(1)

[0655] Iodomethane (554 mg) was added to a suspension of(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionoicacid (1.1 g) and potassium carbonate (539 mg) in N,N-dimethylformamide(7 mL). The mixture was stirred for 2 hours at ambient temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated invacuo to give methyl(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate(1.2 g) as an oil.

[0656] NMR (CDCl₃, δ): 1.42 (9H, s), 3.45-3.60 (2H, m), 3.76 (3H, s),4.41 (1H, m), 4.83 (1H, m), 5.12 (2H, s), 5.79 (1H, m), 7.30-7.40 (5H,m).

[0657] Preparation 78(2)

[0658] Sodium borohydride (251 mg) was added to a solution of methyl(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate(1.17 g) in methanol (10 mL) at 0° C. The mixture was stirred for anhour at the same temperature and then for an hour at ambienttemperature. After addition of 3.6% hydrochloric acid, the mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and an aqueous saturated sodium bicarbonate solution. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residual crystals were suspended in hotdiisopropyl ether and cooled to ambient temperature with stirring. Theresidual crystals were collected by filtration and washed withdiisopropyl ether to give(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanol (945mg) as white crystals.

[0659] NMR (CDCl₃, δ): 1.44 (9H, s), 3.18-3.40 (2H, m), 3.46-3.75 (4H,m), 4.90 (1H, m), 5.09 (2H, s), 5.35 (1H, d, J=5 Hz), 7.30-7.40 (5H, m)

[0660] Mass: (ESI−) 323 (M−H).

[0661] Preparation 78(3)

[0662] 10% Palladium on activated carbon (10 mg) was added to a solutionof (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanol(920 mg) in methanol (10 mL) and dioxane (1 mL). The mixture was stirredunder hydrogen atmosphere (3.5 atm) for one and a half days at ambienttemperature. The catalyst was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was dissolved in ethyl acetate, driedover magnesium sulfate, and concentrated in vacuo to give(S)-2-amino-3-(tert-butoxycarbonylamino)propanol (571 mg) as a whitesolid substance.

[0663] NMR (CDCl₃, δ): 1.45 (9H, s), 2.90 (1H, m), 3.18 (2H, m), 3.49(2H, m), 4.90 (1H, br)

[0664] Mass: (ESI+) 191(M+H), (ESI−) 189(M−H).

EXAMPLE 78(1)

[0665](S)-2-{1-[tert-(Butoxycarbonyl)aminomethyl]-2-hydroxyethylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(719 mg) was obtained as yellow crystals fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (930 mg) and(S)-2-amino-3-(tert-butoxycarbonylamino)propanol (556 mg) in a mannersimilar to Example 1(1).

[0666] NMR (DMSO-d₆, δ): 1.36 (9H, s), 3.08 (2H, m), 3.53 (1H, m), 3.73(3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6 Hz), 4.99 (1H, t, J=6 Hz), 6.84(1H, brd, J=8 Hz), 6.90-7.06 (4H, m), 8.09 (1H, dd, J=2, 9 Hz), 8.58 (H,d, J=2 Hz), 9.20 (1H, d, J=9 Hz), 9.26 (1H, t, J=6 Hz)

[0667] Mass: (ESI−) 503 (M−H).

EXAMPLE 78(2)

[0668](S)-2-{1-[tert-(Butoxycarbonyl)aminomethyl]-2-hydroxyethylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(618 mg) was dissolved in pyridine (5 mL) and acetic anhydride (2 mL).The mixture was stirred at ambient temperature overnight, thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand 3.6% hydrochloric acid. The organic layer was washed with an aqueoussaturated sodium bicarbonate solution and brine, dried over magnesiumsulfate and concentrated in vacuo. 4N-Hydrogen chloride solution inethyl acetate (5 mL) was added to the residue and the mixture wasstirred at ambient temperature for 2 hours. The mixture was concentratedin vacuo, and the residue was partitioned between ethyl acetate and anaqueous saturated sodium bicarbonate solution. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated invacuo. The residue was purified by a silica gel column chromatographyeluting with 5% methanol in chloroform and then a mixture of 28%ammonium hydroxide, methanol and chloroform (1:10:100) to give (S)-2-l1-(acetylaminomethyl)-2-hydroxyethylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(171 mg) as yellow crystals;

[0669] NMR (DMSO-d₆, δ): 1.80 (3H, s), 3.09-3.30 (2H, m), 3.48-3.60 (2H,m), 3.66-3.78 (1H, m), 3.73 (3H, s), 3.75 (3H, s), 4.37 (2H, d, J=6 Hz),5.04 (1H, t, J=5 Hz), 6.85 (1H, dd, J=2, 8 Hz), 6.91 (1H, d, J=8 Hz),6.96 (1H, d, J=2 Hz), 7.08 (1H, d, J=9 Hz), 8.07-8.15 (2H, m), 8.58 (1H,d, J=3 Hz), 9.20 (1H, d, J=8 Hz), 9.28 (1H, t, J=-6 Hz)

[0670] Mass: (ESI+) 447 (M+H), (ESI−) 445 (M−H), and(S)-2-[1-(aminomethyl)-2-hydroxyethylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(178 mg) as amorphous powders.

[0671] NMR (DMSO-d₆, δ): 2.73 (2H, m), 3.47-3.64 (3H, m), 3.73 (3H, s),3.74 (3H, s), 4.36 (2H, s), 6.85 (1H, dd, J=2, 8 Hz), 6.90-7.00 (3H, m),8.09 (1H, dd, J=3, 9 Hz), 8.56 (1H, d, J=3 Hz), 9.15-9.33 (2H, m)

[0672] Mass: (ESI+) 405(M+H).

EXAMPLE 78(3)

[0673](S)-N-(3,4-Dimethoxybenzyl)-2-[1-(formamidomethyl)-2-hydroxyethylamino]-5-nitrobenzamide(112 mg) was obtained as yellow crystals from(S)-2-[1-(aminomethyl)-2-hydroxyethylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(147 mg) in a manner similar to Example 73(2).

[0674] NMR (DMSO-d₆, δ): 3.26 (2H, m), 3.54 (2H, m), 3.65-3.84 (1H, m),3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=6 Hz), 5.06 (1H, t, J=5 Hz),6.85 (1H, brd, J=8 Hz), 6.91 (1H, d, J=8 Hz), 6.96 (1H, br), 7.06 (1H,d, J=9 Hz), 8.05 (1H, s), 8.11 (1H, dd, J=3, 9 Hz), 8.25 (1H, t, J=5Hz), 8.60 (1H, d, J=3 Hz), 9.21 (1H, d, J=7 Hz), 9.29 (1H, t, J=6 Hz)

[0675] Mass: (ESI+) 433 (M+H), (ESI−) 431 (M−H).

[0676] Preparation 79(1)

[0677] Diphenylphosphorylazide (2.60 g) was added dropwise to a mixtureof N-(tert-butoxycarbonyl)nipecotic acid (2.06 g) and triethylamine(1.00 g) in toluene (20 mL). The reaction mixture was warnied in an oilbath over 10 minutes at 100° C. Stirring was continued for 2 hours at100° C., then the reaction vessel was taken out from the oil bath. Afterreflux was ceased, benzyl alcohol (1.07 g) was added to the reactionmixture. The mixture was stirred for 3 hours at 100° C., and then pouredinto a mixture of 3.6% hydrochloric acid, ice and ethyl acetate. Theseparated organic layer was washed with brine, an aqueous saturatedsodium bicarbonate solution and brine, successively. The resultant wasdried over magnesium sulfate and concentrated in vacuo. The residue waspurified by a silica gel column chromatography eluting with 30% ethylacetate in hexane to give3-(benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine (2.66 g) asan oil.

[0678] NMR (CDCl₃, δ): 1.44 (9H, s), 1.40-2.00 (4H, m), 3.09-3.45 (3H,m), 3.59 (1H, brd, J=13 Hz), 3.70 (1H, br), 4.70 and 4.88 (1H, m), 5.10(2H, s), 7.27-7.40 (5H, m)

[0679] Mass: (ESI+) 335(M+H), (ESI−) 333(M−H).

[0680] Preparation 79(2)

[0681] 3-Amino-1-tert-butoxycarbonylpiperidine (1.48 g) was obtained assyrup from 3-(benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine(2.54 g) in a manner similar to Preparation 78(3).

[0682] NMR (CDCl₃, δ): 1.30 (1H, m), 1.40-1.60 (1H, m), 1.46 (9H, s),1.70 (1H, m), 1.96 (1H, m), 2.66 (1H, m), 2.75-2.95 (2H, m), 3.80 (1H,m), 3.94 (1H, m)

EXAMPLE 79(1)

[0683]2-[1-(tert-Butoxycarbonyl)piperidin-3-ylamino]-N-(3,4-dirnethoxybenzyl)-5-nitrobenzamide(900 mg) was obtained as amorphous powders fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (700 mg) and3-amino-1-tert-butoxycarbonylpiperidine (503 mg) in a manner similar toExample 1(1).

[0684] NMR (DMSO-d₆, δ): 1.20-2.00 (13H, in), 3.10-3.65 (4H, in),3.65-3.80 (1H, in), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=6 Hz),6.83 (1H, d, J=8 Hz), 6.84-6.96 (3H, m), 8.15 (1H, dd, J=2, 9 Hz), 8.65(1H, s), 9.15-9.45 (1H, in), 9.34 (1H, t, J=6 Hz)

[0685] Mass: (ESI+) 515(M+H), (ESI−) 513(M−H).

EXAMPLE 79(2)

[0686] A mixture of2-[1-(tert-butoxycarbonyl)piperidin-3-ylamino]-N-(3,4-diinethoxybenzyl)-5-nitrobenzamide(190 mg) and 4 N hydrogenchloride solution in ethyl acetate (5 mL) wasstirred for 2 hours at ambient temperature. The reaction mixture wasconcentrated in vacuo. The residual crystals were collected byfiltration and washed with ethyl acetate to giveN-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamidehydrochloride (138 mg) as yellow crystals.

[0687] NMR (DMSO-d₆, δ): 1.55-1.96 (3H, in), 2.04 (1H, m), 2.78-2.92(2H, m), 3.18-3.40 (2H, m), 3.73 (3H, s), 3.75 (3H, s), 3.98 (1H, m),4.39 (2H, d, J=6 Hz), 6.85 (1H, d, J=8 Hz), 6.90-7.00 (3H, m), 8.19 (1H,dd, J=3, 9 Hz), 8.65 (1H, d, J=3 Hz), 9.08 (1H, d, J=8 Hz), 9.41 (1H, t,J=6 Hz)

[0688] Mass: (ESI−) 413(M−H).

EXAMPLE 79(3)

[0689]N-(3,4-Dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-3-ylamino]-5-nitrobenzamide(100 mg) was obtained as yellow crystals fromN-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamidehydrochloride (100 mg) in a manner similar to Example 73(3).

[0690] NMR (DMSO-d₆, δ): 1.50-1.83 (3H, m), 1.87 (1H, m), 2.89 (3H, s),2.95-3.15 (1H, m), 3.01 (1H, dd, J=7, 10 Hz), 3.21 (1H, m), 3.41 (1H,dd, J=4, 10 Hz), 3.73 (3H, s), 3.74 (3H, s), 3.91 (1H, m), 4.38 (2H, d,J=6 Hz), 6.85 (1H, dd, J=2, 8 Hz), 6.90-7.00 (3H, m), 8.16 (1H, dd, J=3,9 Hz), 8.63 (1H, d, J=3 Hz), 9.25 (1H, d, J=8 Hz), 9.35 (1H, t, J=6 Hz)

[0691] Mass: (ESI+) 493(M+H), (ESI−) 491(M−H).

EXAMPLE 79(4)

[0692] N-(3,4-Dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide(550 mg) was obtained as yellow crystals from2-11-(tert-butoxycarbonyl)piperidin-3-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(802 mg) in a manner similar to Example 77(2).

[0693] NMR (DMSO-d₆, δ): 1.36-1.64 (2H, in), 1.82 (1H, m), 2.40-2.65(2H, m), 2.70 (1H, m), 2.96 (1H, dd, J=4, 10 Hz), 3.63 (1H, m), 3.73(3H, s), 3.74 (3H, s), 4.38 (2H, d, J=6 Hz), 6.84-6.93 (3H, m), 6.96(1H, d, J=2 Hz), 8.11 (1H, dd, J=3, 9 Hz), 8.58 (1H, d, J=3 Hz), 9.20(1H, d, J=8 Hz), 9.29 (1H, t, J=6 Hz)

[0694] Mass: (ESI+) 415(M+H), (ESI−) 413(M−H).

EXAMPLE 79(5)

[0695]N-(3,4-Dimethoxybenzyl)-2-(1-formylpiperidin-3-ylamino)-5-nitrobenzamide(102 mg) was obtained as yellow crystals fromN-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide (126mg) in a manner similar to Example 73(2).

[0696] NMR (DMSO-d₆, δ): 1.40-1.76 (3H, m), 1.93-2.05 (1H, m), 3.14-3.86(5H, m), 3.73 (3H, s), 3.75 (3H, s), 4.37 (2H, d, J=SHz), 6.84 (1H, d,J=2.8 Hz), 6.90-7.04 (3H, m), 7.96 and 8.06 (1H, s), 8.13 and 8.16 (1H,d, J=3.9 Hz), 8.63 and 8.64 (1H, d, J=3 Hz), 9.19 and 9.23 (1H, d, J=8Hz), 9.34 and 9.35 (1H, t, J=5 Hz)

[0697] Mass: (ESI+) 443(M+H), (ESI−) 441(M−H).

EXAMPLE 80

[0698]2-(1H-Benzimidazol-5-ylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(130.9 mg) was obtained as a yellow solid substance fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and5-amino-1H-benzimidazole (159 mg) in a manner similar to Example 1(1).

[0699] mp. 226.5-227° C.

[0700] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.75 (3H, s), 4.45 (2H, br), 6.90(1H, d, J=8.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.00 (1H, s), 7.04 (1H, br),7.11 (1H, brd, J=8.SHz), 7.51 (1H, br), 7.64 (1H, br), 8.10 (1H, dd,J=8.5, 2.5 Hz), 8.26 (1H, s), 8.69 (1H, d, J=2.5 Hz), 9.50 (1H, br),10.71 (1H, br), 12.53 (1H, br)

[0701] Mass m/z: 448 (M⁺+1).

EXAMPLE 81 (1)

[0702] 2-[(3S,SS)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide(814 mg) was obtained fromN-(3,4-dimethoxylbenzyl)-2-fluoro-5-nitrobenzamide (513 mg) and methyl(2S, 4S)-4-aniino-1-(tert-butoxycarbonyl)pyrroridine-2-carboxylate (750mg) in a manner similar to Example 1 (1).

[0703] NMR (DMSO-d₆, δ): 1.35 (9×3/5H, s), 1.41 (9×2/5H, s), 1.94 (1H,m), 2.70 (1H, m), 3.21 (1H, dd, J=11, 4 Hz), 3.56 (3×2/5H, s), 3.58(3×3/5H, s), 3.72 (3H, s), 3.74 (3H, s), 3.85 (1H, m), 4.25-4.45 (3H,m), 6.83-6.98 (4H, m), 8.15 (1H, dd, J=9, 2 Hz), 8.61 (1H, d, J=2 Hz),9.06 (1H, m), 9.34 (1H, t, J=6 Hz)

[0704] Mass m/z: 558 (M⁺).

EXAMPLE 81(2)

[0705] A mixture of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxlbenzyl)-5-nitrobenzamide(143 mg) and 30% methanol solution of methylamine (4 mL) was stirred forone day at ambient temperature. After evaporation of the solvent, theresidue was partitioned between ethyl acetate and water. The organiclayer was separated, washed with brine and dried over magnesium sulfate.The residue was subjected to a silica gel column chromatography elutingwith ethyl acetate to give 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methylcarbamoyl)pyrrolidin-3-ylamino]-N-(3 4-dinethoxylbenzyl)-5-nitrobenzamide (149 mg).

[0706] NMR (DMSO-d₆, δ): 1.48 (9H, s), 2.33-2.70 (2H, m), 2.79 (3H, d,J=5 Hz), 3.47 (1H, m), 3.88 (3H, s), 3.90 (3H, s), 4.15 (1H, m), 4.40(1H, m), 4.50 (1H, dd, J=16, 7 Hz), 4.57 (1H, dd, J=16, 7 Hz), 6.58 (1H,m), 6.62 (1H, d, J=9 Hz), 6.83-6.93 (3H, m), 8.16 (1H, dd, J=9, 3 Hz),8.33 (1H, d, J=3 Hz), 8.98 (1H, m)

[0707] Mass m/z: 558 (M⁺).

EXAMPLE 81(3)

[0708] To a solution of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide(492 mg) in tetrahydrofuran (5 mL) was added lithium chloride (75 mg),and then a solution of sodium borohydride (67 mg) in ethanol (10 mL) atambient temperature. After stirring for one day, the mixture wasevaporated and the residue was partitioned between ethyl acetate and 10%citric acid aqueous solution. The organic layer was separated, washedwith water and brine and dried over magnesium sulfate. The residue wassubjected to a silica gel column chromatography eluting with a mixtureof ethyl acetate and hexane (1:1 to 2:1) to give 2-[(3S,SS)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide(399 mg) as pale yellow foams.

[0709] NMR (DMSO-d₆, δ): 1.41 (9H, s), 1.93 (1H, m), 2.44 (1H, m), 3.04(1H, m), 3.51-3.62 (2H, m), 3.70-3.95 (2H, m), 3.73 (3H, s), 3.74 (3H,s), 4.21 (1H, m), 4.38 (2H, d, J=6 Hz), 4.84 (1H, t, J=5 Hz), 6.81-6.97(4H, m), 8.15 (1H, dd, J=10, 3 Hz), 8.60 (1H, d, J=3 Hz), 9.18 (1H, d,J=8 Hz), 9.33 (1H, t, J=6 Hz).

EXAMPLE 81(4)

[0710] A mixture of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylamino-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (326 mg) and 4N-hydrogenchloride solution in ethyl acetate (5 mL) was stirred for one day atambient temperature. After evaporation of the solvent, the residue waspartitioned between chloroform and an aqueous saturated sodiumbicarbonate solution. The organic layer was separated, washed with brineand dried over magnesium sulfate. The filtrate was evaporated to giveN-(3,4-dimethoxylbenzyl)-2-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-5-nitrobenzamide (242 mg) aspale yellow foams.

[0711] NMR (DMSO-d₆, δ): 1.32 (1H, m), 2.35 (1H, m), 2.72 (1H, m), 3.13(1H, m), 3.20-3.41 (2H, m), 3.53 (1H, m), 3.73 (3H, s), 3.74 (3H, s),4.05 (1H, m), 4.38 (2H, d, J=6 Hz), 4.61 (1H, brt, J=5 Hz), 6.80-6.99(4H, m), 8.13 (1H, dd, J=9, 3 Hz), 8.60 (1H, m), 9.13 (1H, m), 9.32 (1H,m)

[0712] Mass (ES) m/z: 431 (M⁺).

EXAMPLE 81 (5)

[0713] N-(3,4-Dimethoxylbenzyl)-2-[(3S,5S)—S-(methylcarbamoyl)pyrrolidin-3-ylamino]-5-nitrobenzamide (75 mg)was obtained as pale yellow foams from 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methylcarbamoyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide(111 mg) in a manner similar to Example 81(4).

[0714] NMR (DMSO-d₆, δ): 1.70 (1H, ddd, J=13, 5, 5 Hz), 2.43 (1H, m),2.53 (3H, d, J=5 Hz), 2.72 (1H, dd, J=10, 4 Hz), 3.26 (1H, dd, J=10, 5Hz), 3.60 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.07 (1H, m), 4.34 (1H,dd, J=15, 6 Hz), 4.40 (1H, dd, J=15, 6 Hz), 6.81-6.97 (4H, m), 7.85 (1H,q, J=5 Hz), 8.14 (1H, dd, J=9, 2 Hz), 8.59 (1H, d, J=2 Hz), 9.07 (1H, d,J=8 Hz), 9.30 (1H, t, J=6 Hz)

[0715] Mass m/z: 458 (M⁺).

[0716] Preparation 82

[0717] To a suspension of cis-4-aminocyclohexanecarboxylic acid (1.04 g)in methanol (25 mL) was added thionyl chloride (0.583 mL) underice-water cooling. The mixture was stirred for an hour at 0° C. and for17 hours at ambient temperature. After evaporation of the solvent, theresidue was triturated with diethyl ether to give methylcis-4-aminocyclohexanecarboxylate hydrochloride as white powders (1.37g).

[0718] NMR (DMSO-d₆, δ): 1.40-1.68 (4H, m), 1.73-1.85 (2H, br),1.93-2.07 (2H, br), 2.62 (1H, m), 3.02-3.14 (1H, br), 3.63 (3H, s), 8.00(3H, br).

EXAMPLE 82(1)

[0719]N-(3,4-Dimethoxybenzyl)-2-[cis-4-(methoxycarbonyl)cyclohexylamino]-5-nitrobenzamide(1.38 g) was obtained as yellow powders fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (1.00 g) and methylcis-4-aminocyclohexanecarboxylate hydrochloride (985 mg) in a mannersimilar to Example 1(1).

[0720] NMR (DMSO-d₆, δ): 1.55-1.85 (8H, br), 2.50-2.60 (1H, br), 3.62(3H, s), 3.73 (3H, s), 3.74 (3H, s), 3.75-3.85 (1H, br), 4.38 (2H, d,J=7 Hz), 6.82-6.98 (4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.62 (1H, d, J=4Hz), 9.28-9.38 (2H, br).

EXAMPLE 82(2)

[0721]2-(cis-4-Carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(1.12 g) was obtained as yellow powders fromN-(3,4-dimethoxybenzyl)-2-[cis-4-(methoxycarbonyl)cyclohexylamino]-5-nitrobenzamide (1.27 g) in a manner similar toExample 23(2).

[0722] NMR (DMSO-d₆, δ): 1.55-1.85 (8H, br), 2.39-2.49 (1H, br), 3.73(3H, s), 3.74 (3H, s), 3.75-3.85 (1H, br), 4.38 (2H, d, J=7 Hz),6.80-7.00 (4H, m), 8.12 (1H, dd, J=4 Hz, 8 Hz), 8.61 (1H, d, J=4 Hz),9.33 (2H, br).

EXAMPLE 82(3)

[0723]N-(3,4-Dimethoxybenzyl)-2-[cis-4-(dimethylcarbamoyl)cyclohexylamino]-5-nitrobenzamide(81.8 mg) was obtained as yellow powders from2-(cis-4-carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(100 mg) and dimethylamine hydrochloride (21.4 mg) in a manner similarto Example 23(3).

[0724] NMR (DMSO-d₆, δ): 1.52-1.90 (8H, br), 2.66-2.76 (1H, br), 2.80(3H, s), 3.02 (3H, s), 3.73 (3H, s), 3.74 (3H, s), 3.85-3.95 (1H, br),4.40 (2H, d, J=7 Hz), 6.83-6.98 (4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.63(1H, d, J=4 Hz), 9.33 (1H, br), 9.50 (1H, d, J=8 Hz)

[0725] Mass m/z: 483 (M⁺).

EXAMPLE 82(4)

[0726]N-(3,4-Dimethoxybenzyl)-2-[cis-4-(2-hydroxyethylcarbamoyl)cyclohexylamino]-5-nitrobenzamide(100 mg) was obtained as yellow powders from2-(cis-4-carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide(100 mg) and 2-aminoethanol (16.0 mg) in a manner similar to Example23(3).

[0727] NMR (DMSO-d₆, δ): 1.55-1.72 (8H, br), 2.20-2.30 (1H, br),3.06-3.16 (2H, m), 3.35-3.41 (2H, m), 3.73 (3H, s), 3.74 (3H, s),3.78-3.88 (1H, br), 4.39 (2H, d, J=7 Hz), 4.65 (1H, t, J=7 Hz),6.83-6.98 (4H, m), 7.74 (1H, br), 8.12 (1H, dd, J=4, 8 Hz), 8.63 (1H, d,J=4 Hz), 9.33 (1H, br), 9.43 (1H, d, J=8 Hz)

[0728] Mass m/z: 499 (M⁺).

[0729] Preparation 83(1)

[0730] 4-(Benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine (5.44g) was obtained as a solid substance fromN-tert-butoxycarbonylisonipecotic acid (4.5 g) in a manner similar toPreparation 79(1).

[0731] NMR (CDCl₃, δ): 1.30 (2H, dq, J=4, 10 Hz), 1.45 (9H, s), 1.94(2H, br d, J=10 Hz), 2.85 (2H, t, J=10 Hz), 3.66 (1H, m), 4.01 (2H, br),4.65 (1H, m), 5.09 (2H, s), 7.27-7.40 (5H, m).

[0732] Preparation 83(2)

[0733] 4-Amino-1-tert-butoxycarbonylpiperidine (3.83 g) was obtained assyrup from 4-(benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine(5.11 g) in a manner similar to Preparation 78(3).

[0734] NMR (CDCl₃, δ): 1.30 (2H, m), 1.83 (2H, m), 2.56 (2H, m),2.60-2.95 (3H, m), 4.06 (2H, m)

[0735] Mass: (ESI+) 201(M⁺+1).

EXAMPLE 83(1)

[0736]2-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(360 mg) was obtained as amorphous powders from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (300 mg) and4-amino-1-tert-butoxycarbonylpiperidine (287 mg) in a manner similar toExample 1 (1).

[0737] NMR (DMSO-d₆, δ): 1.28 (2H, m), 1.90 (2H, m), 3.00 (2H, m),3.61-3.75 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 3.80 (2H, m), 4.35 (2H,d, J=6 Hz), 6.83 (1H, dd, J=2, 8 Hz), 6.88-6.94 (3H, m), 7.63 (1H, dd,J=2, 9 Hz), 8.07 (1H, d, J=2 Hz), 8.71 (1H, d, J=8 Hz), 9.03 (1H, t, J=6Hz)

[0738] Mass: (ESI−) 493(M−H).

EXAMPLE 83(2)

[0739] 5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamidehydrochloride (254 mg) was obtained as white crystals from2-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(297 mg) in a manner similar to

EXAMPLE 79(2).

[0740] NMR (DMSO-d₆, δ): 1.60 (2H, m), 2.10 (2H, m), 3.01 (2H, m), 3.26(2H, m), 3.64-3.87 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.89-7.00 (3H, m), 7.67 (1H, dd, J=2, 8Hz), 8.12 (1H, d, J=2 Hz), 8.70-9.05 (2H, m), 9. 11 (1H, t, J=6 Hz)

[0741] Mass: (ESI+) 395(M+H), (ESI−) 393(M−H).

EXAMPLE 83(3)

[0742] 5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamidehydrochloride (100 mg) was partitioned between ethyl acetate and anaqueous saturated sodium bicarbonate solution. The organic layer wasseparated, dried over magnesium sulfate and concentrated in vacuo. Theresidue was dissolved in N,N-dimethylformamide (1 mL), and ethyl formate(5 mL) was added to the solution. The mixture was refluxed under heatingovernight and partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was crystallized from ethyl acetateto give5-cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpiperidin-4-ylamino)benzamide(52 mg) as white crystals.

[0743] NMR (DMSO-d₆, δ): 1.15-1.44 (2H, m), 1.88-2.03 (2H, m), 2.91 (1H,m), 3.16-3.35 (2H, m), 3.60-3.85 (2H, m), 3.72 (3H, s), 3.74 (3H, s),4.01 (1H, m), 4.35 (2H, d, J=5 Hz), 6.83 (1H, dd, J=2, 8 Hz), 6.84-6.97(3H, m), 7.64 (1H, dd, J=2, 9 Hz), 7.99 (1H, s), 8.07 (1H, d, J=2 Hz),8.74 (1H, d, J=8 Hz), 9.03 (1H, t, J=5 Hz)

[0744] Mass: (ESI−) 421(M−H).

EXAMPLE 83(4)

[0745]5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-4-ylamino)benzamide(78 mg) was obtained as white crystals from5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamidehydrochloride (100 mg) in a manner similar to Example 73(3).

[0746] NMR (DMSO-d₆, δ): 1.48 (2H, m), 2.02 (2H, m), 2.89 (3H, s), 2.96(2H, m), 3.50 (2H, m), 3.64 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35(2H, d, J=5 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.88-6.96 (3H, m), 7.65 (1H,d, J=2, 9 Hz), 8.08 (1H, d, J=2 Hz), 8.73 (1H, d, J=8 Hz), 9.04 (1H, t,J=5 Hz)

[0747] Mass: (ESI−) 471(M−H).

EXAMPLE 84(1)

[0748]2-[1-(tert-Butoxycarbonyl)piperidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(368 mg) was obtained as amorphous powders from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (300 mg) and3-amino-1-tert-butoxycarbonylpiperidine (249 mg) in a manner similar toExample 1(1).

[0749] NMR (DMSO-d₆, δ): 1.10-1.75 (12H, m), 1.88 (1H, m), 2.95-3.65(5H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d, J=6 Hz), 6.80-6.96(4H, m), 7.65 (1H, d, J=9 Hz), 8.10 (1H, s), 8.75-9.10 (1H, m), 9.03(1H, t, J=6 Hz)

[0750] Mass: (ESI−) 493(M−H).

EXAMPLE 84(2)

[0751] 5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide(283 mg) was obtained as an oil from 2-[1-(tert-butoxycarbonyl)piperidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (311 mg) in amanner similar to Example 77(2).

[0752] NMR (DMSO-d₆, δ): 1.44 (2H, m), 1.58 (1H, m), 1.82 (1H, m), 2.45(1H, dd, J=7, 10 Hz), 2.56 (1H, m), 2.71 (1H, m), 2.97 (1H, dd, J=4, 10Hz), 3.52 (1H, in), 3.72 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6 Hz),6.80-6.95 (4H, m), 7.60 (1H, dd, J=3, 9 Hz), 8.04 (1H, d, J=3 Hz), 8.78(1H, d, J=8 Hz), 8.98 (1H, t, J=6 Hz)

[0753] Mass: (ESI+) 395(M+H), (ESI−) 393(M−H).

EXAMPLE 84(3)

[0754]5-Cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpiperidin-3-ylamino)benzamide(61 mg) was obtained as amorphous powders from5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide (94 mg)in a manner similar to Example 73(2).

[0755] NMR (DMSO-d₆, δ): 1.40-1.75 (3H, m), 3.06-3.84 (5H, m), 3.72 (3H,s), 3.74 (3H, s), 4.36 (2H, d, J=6 Hz), 6.80-7.01 (4H, m), 7.63 and 7.67(1H, d, J=9 Hz), 7.95 and 8.05 (1H, s), 8.08 (1H, br), 8.80 and 8.84(1H, d, J=8 Hz), 9.04 (1H, t, J=6 Hz)

[0756] Mass: (ESI+) 423(M+H), (ESI−) 421(M−H).

EXAMPLE 84(4)

[0757]5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-3-ylamino]benzamide(83 mg) was obtained as white crystals from5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide (82 mg)in a manner similar to Example 73(3).

[0758] NMR (DMSO-d₆, δ): 1.44-1.94 (4H, m), 2.8-2.96 (1H, m), 2.88 (3H,s), 3.04 (1H, m), 3.22 (1H, m), 3.42 (1H, in), 3.72 (3H, s), 3.74 (3H,s), 3.80 (1H, m), 4.36 (2H, d, J=5 Hz), 6.84 (1H, d, J=2, 8 Hz),6.88-6.92 (2H, m), 6.94 (1H, d, J=2 Hz), 7.66 (1H, dd, J=2, 9 Hz), 8.08(1H, d, J=2 Hz), 8.85 (1H, d, J=8 Hz), 9.04 (1H, t, J=5 Hz)

[0759] Mass: (ESI+) 473(M+H), 495(M+Na), (ESI−) 471(M−H).

[0760] Preparation 85(1)

[0761] A solution of di-tert-butyl dicarbonate (5.44 g) in dioxane (10mL) was added dropwise to a solution of(S)-3-benzyloxycarbonylaminopyrrolidine (3.66 g) in dioxane (10 mL)under cooling on an ice bath. The reaction mixture was stirred atambient temperature overnight, then the reaction was quenched byaddition of 3-(N,N-dimethylamino)propylamine (5 mL). The mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and 3.6% hydrochloric acid. The organic layer was washed with anaqueous saturated sodium bicarbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bya silica gel column chromatography eluting with 30% ethyl acetate inhexane to give(S)-3-benzyloxycarbonylamino-1-tert-butoxycarbonylpyrrolidine (1.26 g)as an oil.

[0762] NMR (CDCl₃, δ): 1.45 (9H, s), 1.84 (1H, m), 2.14 (1H, m), 3.20(1H, m), 3.33-3.50 (2H, m), 3.61 (1H, dd, J=2, 10 Hz), 4.25 (1H, m),4.85 (1H, m), 5.10 (2H, s), 7.27-7.41 (5H, m)

[0763] Mass: (ESI+) 321(M+H).

[0764] Preparation 85(2) (S)-3-Amino-1-tert-butoxycarbonylpyrrolidine(2.49 g) was obtained as syrup from(S)-3-benzyloxycarbonylamino-1-tert-butoxycarbonylpyrrolidine (4.10 g)in a manner similar to Preparation 78(3).

[0765] NMR (DMSO-d₆, δ): 1.39 (9H, s), 1.57 (1H, m), 1.88 (1H, m), 2.89(1H, dd, J=5, 1 lHz), 3.00-3.40 (3H, m), 3.42 (1H, m)

[0766] Mass: (ESI+) 187(M+H).

EXAMPLE 85(1)

[0767](S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(368 mg) was obtained as amorphous powders from5-cyano-N-(3,4-dimethoxyb enzyl)-2-fluorobenzamide (500 mg) and(S)-3-amino-1-tert-butoxycarbonylpyrrolidine (593 mg) in a mannersimilar to Example 1(1).

[0768] NMR (DMSO-d₆, δ): 1.82 (1H, m), 2.20 (1H, m), 3. 10 (1H, m),3.25-3.45 (2H, m), 3.61 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.18 (1H,m), 4.35 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.80-6.94 (3H, m),7.66 (1H, dd, J=2, 8 Hz), 96 8.09 (1H, d, J=2 Hz), 8.82 (1H, d, J=7 Hz),9.05 (1H, t, J=6 Hz).

EXAMPLE 85(2)

[0769](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(201 mg) was obtained as amorphous powders from(S)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino}-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(277 mg) in a manner similar to Example 77(2).

[0770] NMR (DMSO-d₆, δ): 1.50 (1H, m), 2.11 (1H, m), 2.57 (1H, dd, J=4,10 Hz), 2.70-2.95 (2H, m), 3.13 (1H, dd, J=6, 10 Hz), 3.72 (3H, s), 3.74(3H, s), 3.96 (1H, m), 4.34 (2H, d, J=6 Hz), 6.78-6.94 (4H, m), 7.64(1H, dd, J=2, 8 Hz), 8.06 (1H, d, J=2 Hz), 8.72 (1H, d, J=7 Hz), 9.02(1H, t, J=6 Hz)

[0771] Mass: (ESI+) 381(M+H), (ESI−) 379(M−H).

EXAMPLE 85(3)

[0772](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)pyrrolidin-3-ylamino)benzamide(81 mg) was obtained as white crystals from(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) in a manner similar to Example 73(3).

[0773] NMR (DMSO-d₆, δ): 1.89 (1H, m), 2.30 (1H, m), 2.90 (3H, s), 3.09(1H, dd, J=4, 10 Hz), 3.28-3.45 (2H, m), 3.62 (1H, dd, J=6, 10 Hz), 3.72(3H, s), 3.74 (3H, s), 4.25 (1H, m), 4.36 (2H, d, J=6 Hz), 6.84 (1H, dd,J=2, 8 Hz), 6.85-6.94 (3H, m), 7.68 (1H, d, J=2, 8 Hz), 8.09 (1H, d, J=2Hz), 8.84 (1H, d, J=7 Hz), 9.07 (1H, t, J=6 Hz)

[0774] Mass: (ESI+) 459(M+H), (ESI−) 457(M−H).

EXAMPLE 85(4)

[0775](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpyrrolidin-3-ylamino)benzamide(89 mg) was obtained as amorphous powders from(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) in a manner similar to Example 73(2).

[0776] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.25 (1H, m), 3.15(ca.0.5H, dd,J=4, 10 Hz), 3.25-3.75 (3H, m), 3.72 (3H, s), 3.74 (3H, s),3.84(ca.0.5H, dd, J=6, 10 Hz), 4.13-4.29 (1H, m), 4.35 (1H, d, J=6 Hz),6.83 (1H, d, J=8 Hz), 6.88-6.96 (3H, m), 7.68 (1H, dd, J=2, 8 Hz), 8.10(1H, d, J=2 Hz), 8.17 and 8.19 (1H, s), 8.82 (1H, d, J=7 Hz), 9.06 (1H,t, J=6 Hz)

[0777] Mass: (ESI+) 409(M+H), (ESI−) 407(M−H).

EXAMPLE 85(5)

[0778] A solution of methyl chloroformate (26 mg) in chloroform (2 mL)was added dropwise to a mixture of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino) benzamide (80 mg) and triethylamine(43 mg) in a mixture of chloroform (2 mL) and1,3-dimethyl-2-imidazolidinone (1 mL) under cooling on an ice bath. Thereaction mixture was stirred for 2 hours at same temperature and thereaction was quenched by addition of 3-(N,N-dimethylamino)propylamine(0.1 mL). The mixture was concentrated in vacuo, and the residue waspartitioned between ethyl acetate and 3.6% hydrochloric acid. Theorganic layer was washed with an aqueous saturated sodium bicarbonatesolution and brine, dried over magnesium sulfate and concentrated invacuo. The residue was purified by a silica gel column chromatographyeluting with 70% ethyl acetate in hexane. The obtained crystals wererecrystallized from a mixture of 2-propanol and diisopropyl ether togive(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylamino]benzamide(55 mg) as white crystals.

[0779] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.21 (1H, m), 3.16 (1H, m),3.30-3.50 (2H, m), 3.55-3.80 (1H, m), 3.57 and 3.59 (3H, s), 3.72 (3H,s), 3.74 (3H, s), 4.20 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d, J=2,8 Hz), 6.88-6.94 (3H, m), 7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d, J=2Hz), 8.83 (1H, d, J=7 Hz), 9.06 (1H, t, J=6 Hz)

[0780] Mass: (ESI−) 437(M−H).

EXAMPLE 85(6)

[0781] Acetic anhydride (64 mg) was added to a solution of(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino) benzamide(80 mg) in pyridine (1 mL). The mixture was stirred for an hour atambient temperature. The mixture was partitioned between ethyl acetateand 1% hydrochloric acid. The organic layer was washed with an aqueoussaturated sodium bicarbonate solution and brine. The resultant was driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by a thin layer chromatography developed with 5% methanol inchloroform to give(S)-2-(1-acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(62 mg) as amorphous powders.

[0782] NMR (DMSO-d₆, δ): 1.72-1.88 (1H, m), 1.92 and 1.95 (3H, s),2.13-2.36 (1H, m), 3.20(ca.0.5H, dd, J=3, 12 Hz), 3.27(ca.0.5H, dd, J=5,10 Hz), 3.35-3.60 (4H, m), 3.63(ca.0.5H, dd, J=6, 12 Hz), 3.72 (3H, s),3.74 (3H, s), 3.85(ca.0.5H, dd, J=4, 10 Hz), 4.18 and 4.26 (1H, m), 4.35(2H, d, J=6 Hz), 6.83 (1H, dd, J=2, 8 Hz), 6.80-6.96 (3H, m), 7.67 (1H,dd, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.81 and 8.86 (1H, d, J=6 Hz),9.06 (1H, t, J=6 Hz)

[0783] Mass: (ESI+) 423(M+H), (ESI−) 421(M−H).

EXAMPLE 86

[0784](R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(tetrahydrofuran-3-ylamino)benzamide(96 mg) was obtained from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (126 mg) and(R)-3-aminotetrahydrofuran toluene-4-sulfonate (135 mg) in a mannersimilar to Example 1(1).

[0785] NMR (DMSO-d₆, δ): 1.74 (1H, m), 2.27 (1H, m), 3.54 (1H, dd, J=3,9 Hz), 3.70-3.92 (3H, m), 3.72 (3H, s), 3.74 (3H, s), 4.20 (1H, m), 4.35(2H, d, J=6 Hz), 6.81-6.95 (4H, m), 7.66 (1H, dd, J=2, 9 Hz), 8.08 (1H,d, J=2 Hz), 8.81 (1H, d, J=7 Hz), 9.05 (1H, t, J=6 Hz)

[0786] Mass m/z: 380 (M⁺−1).

EXAMPLE 87(1)

[0787](R)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(918 mg) was obtained as amorphous powders from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (700 mg) and(R)-3-amino-1-tert-butoxycarbonylpyrrolidine (830 mg) in a mannersimilar to Example 1(1).

[0788] NMR (DMSO-d₆, δ): 1.82 (1H, m), 2.20 (1H, m), 3.10 (1H, m),3.25-3.45 (2H, m), 3.61 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.18 (1H,m), 4.35 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.80-6.94 (3H, m),7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.82 (1H, d, J=7 Hz),9.05 (1H, t, J=6 Hz).

EXAMPLE 87(2)

[0789] Trifluoroacetic acid (5 mL) was added to a solution of(R)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (918 mg)in chloroform (5 mL). The mixture was stirred for 4 hours at ambienttemperature and concentrated in vacuo. The residue was partitionedbetween chloroform and an aqueous saturated sodium bicarbonate solution.The organic layer was dried over magnesium sulfate and concentrated invacuo to give(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(610 mg) as amorphous powders.

[0790] NMR (DMSO-d₆, δ): 1.50 (1H, m), 2.11 (1H, m), 2.57 (1H, dd, J=4,10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10 Hz), 3.72 (3H, s), 3.74(3H, s), 3.96 (1H, m), 4.34 (2H, d, J=6 Hz), 6.78-6.94 (4H, m), 7.64(1H, dd, J=2, 8 Hz), 8.06 (1H, d, J=2 Hz), 8.72 (1H, d, J=7 Hz), 9.02(1H, t, J=6 Hz).

EXAMPLE 87(3)

[0791](R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)pyrrolidin-3-ylamino]benzamide(93 mg) was obtained as white crystals from(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(114 mg) in a manner similar to Example 73(3).

[0792] NMR (DMSO-d₆, δ): 1.89 (1H, m), 2.30 (1H, m), 2.90 (3H, s), 3.09(1H, dd, J=4, 10 Hz), 3.28-3.45 (2H, m), 3.62 (1H, dd, J=6, 10 Hz), 3.72(3H, s), 3.74 (3H, s), 4.25 (1H, m), 4.36 (2H, d, J=6 Hz), 6.84 (1H, dd,J=2, 8 Hz), 6.85-6.94 (3H, m), 7.68 (1H, d, J=2, 8 Hz), 8.09 (1H, d, J=2Hz), 8.84 (1H, d, J=7 Hz), 9.07 (1H, t, J=6 Hz).

EXAMPLE 87(4)

[0793](R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylaminoJbenzamide (94 mg) was obtained as powders from(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(116 mg) in a manner similar to Example 85(5).

[0794] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.21 (1H, m), 3.16 (1H, m),3.30-3.50 (2H, m), 3.55-3.80 (1H, m), 3.57 and 3.59 (3H, s), 3.72 (3H,s), 3.74 (3H, s), 4.20 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d, J=2,8 Hz), 6.88-6.94 (3H, m), 7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d, J=2Hz), 8.83 (1H, d, J=7 Hz), 9.06 (1H, t, J=6 Hz).

EXAMPLE 87(5)

[0795](R)-2-(1-Acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(66 mg) was obtained as amorphous powders from(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) in a manner similar to Example 85(6).

[0796] NMR (DMSO-d₆, δ): 1.72-1.88 (1H, m), 1.92 and 1.95 (3H, s),2.13-2.36 (1H, m), 3.20(ca.0.5H, dd, J=3, 12 Hz), 3.27(ca.0.5H, dd, J=5,10 Hz), 3.35-3.60 (4H, m), 3.63(ca.0.5H, dd, J=6, 12 Hz), 3.72 (3H, s),3.74 (3H, s), 3.85(ca.0.5H, dd, J=4, 10 Hz), 4.18 and 4.26 (1H, m), 4.35(2H, d, J=6 Hz), 6.83 (1H, dd, J=2, 8 Hz), 6.80-6.96 (3H, m), 7.67 (1H,dd, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.81 and 8.86 (1H, d, J=6 Hz),9.06 (1H, t, J=6 Hz).

EXAMPLE 87(6)

[0797](R)-5-Cyano-N-(3,4-dirnethoxybenzyl)-2-(1-formylpyrrolidin-3-ylamino)benzamide(52 mg) was obtained as amorphous powders from(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) in a manner similar to Example 73(2).

[0798] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.25 (1H, m), 3.15(ca.0.5H, dd,J=4, 10 Hz), 3.25-3.75 (3H, m), 3.72 (3H, s), 3.74 (3H, s),3.84(ca.0.5H, dd, J=6, 10 Hz), 4.13-4.29 (1H, m), 4.35 (1H, d, J=6 Hz),6.83 (1H, d, J=8 Hz), 6.88-6.96 (3H, m), 7.68 (1H, dd, J=2, 8 Hz), 8.10(1H, d, J=2 Hz), 8.17 and 8.19 (1H, s), 8.82 (1H, d, J=7 Hz), 9.06 (1H,t, J=6 Hz).

EXAMPLE 87(7)

[0799] A solution of potassium cyanate (53 mg) in water (1.5 mL) wasadded to a solution of(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) in acetic acid (1.5 mL). The mixture was stirred for 3 hours at60° C. and then for 2 hours at 90° C. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between chloroformand an aqueous saturated sodium bicarbonate solution. The organic layerwas dried over magnesium sulfate and concentrated in vacuo. The residuewas purified by thin layer chromatography developed with 5% methanol inchloroform. The obtained product was triturated with diethyl ether togive(R)-2-(1-carbamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(22 mg) as a powders.

[0800] NMR (DMSO-d₆, δ): 1.83 (1H, m), 2.20 (1H, m), 3.12(1H, dd, J=4,10 Hz), 3.20-3.45 (2H, m), 3.57 (1H, dd, J=6, 10 Hz), 3.72 (3H, s), 3.74(3H, s), 4.19 (1H, m), 4.35 (2H, d, J=6 Hz), 5.80 (2H, s), 6.84 (1H, dd,J=2, 8 Hz), 6.87-6.95 (3H, m), 7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d,J=2 Hz), 8.83 (1H, d, J=7 Hz), 9.05 (1H, t, J=6 Hz)

[0801] Mass: (ESI+) 424(M+H).

EXAMPLE 87(8)

[0802] A solution of benzyl alcohol (28 mg) in 1,2-dichloroethane (1 mL)was added dropwise to a solution of chlorosulfonyl isocyanate (37 mg) in1,2-dichloroethane (2 mL) under 5° C. on an ice-salt bath. The mixturewas stirred for one and a half hours at 4° C. To the mixture was addeddropwise a mixture of(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide(100 mg) and triethylamine (40 mg) in 1,2-dichloroethane (3 mL) under 5°C. After addition, the reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was washed withbrine, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by a thin layer chromatography developed with 5%methanol in chloroform. The obtained product was triturated with diethylether to give(R)-2-[1-(N-benzyloxycarbonylsulfamoyl)pyrrolidin-3-ylamino-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (65 mg) as a syrup.

[0803] NMR (DMSO-d₆, δ): 1.84 (1H, m), 2.22 (1H, in), 3.21 (1H, dd, J=4,10H 3.40-3.55 (2H, m), 3.65-3.80 (1H, m), 3.71 (3H, s), 3.72 (3H, s),4.20 (1H, m), 4.36 (2H, d, J=6 Hz), 5.08 (2H, s), 6.83 (1H, dd, J=2, 8Hz), 6.89 (1H, d, J=8 Hz), 6.93 (1H, d, J=2 Hz), 7.25-7.45 (6H, m), 7.68(1H, dd, J=2, 8 Hz), 8.11 (1H, d, J=2 Hz), 8.85 (1H, d, J=7 Hz), 9.06(1H, t, J=6 Hz)

[0804] Mass: (ESI+) 594(M+H), (ESI−) 593(M−H).

EXAMPLE 87(9)

[0805](R)-2-(1-Sulfamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(26 mg) was obtained as white crystals from(R)-2-[1-(N-benzyloxycarbonylsulfainoyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(60 mg) in a manner similar to

[0806] Preparation 78(3).

[0807] NMR (DMSO-d₆, δ): 1.79 (1H, m), 2.29 (1H, m), 2.94 (1H, dd, J=5,10 Hz), 3.15-3.30 (2H, m), 3.51 (1H, dd, J=7, 10 Hz), 3.72 (3H, s), 3.74(3H, s), 4.22 (1H, m), 4.36 (2H, d, J=6 Hz), 6.80-6.95 (6H, m), 7.67(1H, dd, J=2, 9 Hz), 8.10 (1H, d, J=2 Hz), 8.85 (1H, d, J=7 Hz), 9.07(1H, t, J=6 Hz).

[0808] Preparation 88(1)

[0809] To a solution of 5-bromo-2-fluorobenzaldehyde (10 g) indimethylformamide (60 mL) were added zinc cyamide (6.92 g) andtetrakis(triphenylphosphine)palladium(0) (2.28 g), and the mixture wasstirred at 80° C. for 6 hours. The resulting mixture was diluted withethyl acetate and washed successively with water and brine. The organiclayer was dried over sodium sulfate and evaporated in vacuo. The residuewas subjected to a silica gel column chromatography eluting with amixture of hexane and ethyl acetate (3:1) to give5-cyano-2-fluorobenzaldehyde (5.3 g) as a solid substance.

[0810] NMR (DMSO-d₆, δ): 7.35 (1H, t, J=9 Hz), 7.91 (1H, m), 8.22 (1H,dd, J=2, 7 Hz), 10.36 (1H, s)

[0811] Mass m/z: 150 (M⁺+1).

[0812] Preparation 8(2)

[0813] To a solution of 5-cyano-2-fluorobenzaldehyde (145 mg) inacetonitrile (2 mL) were added a sodium dihydrogenphosphate aqueoussolution (23 mg in 1 mL water) and 30% hydrogen peroxide (0.09 mL). Tothe resulting mixture was added dropwise a sodium chlorite aqueoussolution (126 mg in 1 mL water) for an hour at 0° C. The mixture wasstirred for an hour at ambient temperature, then a small amount ofsodium sulfite was added. The mixture was diluted with ethyl acetate andwashed successively with 1N-hydrochloric acid and brine. The organiclayer was dried over sodium sulfate and evaporated in vacuo. The residuewas triturated with diisopropyl ether to give 5-cyano-2-fluorobenzoicacid (137 mg) as a solid substance.

[0814] NMR (DMSO-d₆, δ): 7.29 (1H, t, J=9 Hz), 7.83 (1H, m), 8.32 (H,dd, J=2, 7 Hz)

[0815] Mass m/z: 164 (M⁺−1).

[0816] Preparation 88(3)

[0817] 5-Cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (228 mg) wasobtained from 5-cyano-2-fluorobenzoic acid (130 mg) and veratrylamine(0.14 mL) in a manner similar to Preparation 1.

[0818] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.75 (3H, s), 4.40 (2H, d, J=6Hz), 6.82-6.96 (3H, m), 7.56 (1H, t, J=9 Hz), 8.04 (1H, m), 8.11 (1H,dd, J 2, 6 Hz), 9.02 (1H, t, J=6 Hz)

[0819] Mass m/z: 313 (M⁺−1).

EXAMPLE 88(1)

[0820](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide(112 mg) was obtained from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (120 mg) and(S)-2-amino-1-propanol (0.09 mL) in a manner similar to Example 1(1).

[0821] mp 142-143.5° C.

[0822] NMR (DMSO-d₆, δ); 1.13 (3H, d, J=6 Hz), 3.42 (2H, t, J=5 Hz),3.67 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.34 (2H, d, J=5 Hz), 4.92(1H, t, J=5 Hz), 6.81-6.95 (4H, m), 7.60 (1H, dd, J=2, 9 Hz), 8.03 (1H,d, J=2 Hz), 8.69 (1H, d, J=8 Hz), 8.97 (1H, t, J=5 Hz)

[0823] Mass m/z: 368 (M⁺−1).

EXAMPLE 88(2)

[0824] To a solution of(S)-5-cyano-N-(3,4-dirnethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide(177 mg) in dimethylformamide (4 mL) was added sodium hydride (19.2 mg)at ambient temperature. After stirring for 20 minutes,4-fluorobenzonitrile (63.8 mg) was added to the mixture. After stirringfor an hour at 60° C., the mixture was diluted with ethyl acetate andwashed successively with water and brine. The organic layer was driedover sodium sulfate and evaporated in vacuo. The residue was subjectedto a silica gel column chromatography eluting with the mixture ofchloroform and ethyl acetate (9:1) to give(S)-5-cyano-2-[2-(4-cyanophenoxy)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide(76 mg) as a solid substance.

[0825] NMR (DMSO-d₆, δ): 1.28 (3H, d, J=7 Hz), 3.49 (2H, m), 3.72 (3H,s), 3.73 (3H, s), 4.13 (3H, m), 4.34 (2H, d, J=6 Hz), 6.80-6.95 (4H, m),7.09 (2H, d, J=9 Hz), 7.63 (1H, dd, J=2, 9 Hz), 7.76 (2H, d, J=9 Hz),8.06 (1H, d, J=2 Hz), 8.83 (1H, d, J=8 Hz), 9.02 (1H, t, J=6 Hz)

[0826] Mass m/z: 469 (M⁺−1).

EXAMPLE 88(3)

[0827] To a solution of(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide(4 g) in pyridine (20 mL) was added methanesulfonyl chloride (1.36 g),and the mixture was stirred for an hour at 0° C. The resulting mixturewas diluted with ethyl acetate and washed successively with water andbrine. The organic layer was dried over sodium sulfate and evaporated invacuo. The residue was triturated with diisopropyl ether to give(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(methanesulfonyloxy)-1-methylethylamino]benzamide(5.43 g) as an oil.

[0828] NMR (DMSO-d₆, δ): 1.22 (3H, d, J=7 Hz), 3.17 (3H, s), 3.72 (3H,s), 3.74 (3H, s), 4.08 (1H, m), 4.23 (2H, d, J=5 Hz), 4.36 (2H, d, J=6Hz), 6.81-6.96 (4H, m), 7.66 (1H, dd, J=2, 9 Hz), 8.08 (1H, d, J=2 Hz),8.74 (1H, d, J=8 Hz), 9.05 (1H, t, J=6 Hz)

[0829] Mass m/z: 448 (M⁺+1).

EXAMPLE 88(4)

[0830] Triphenylphosphine (156 mg) was added to a mixture of(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide(200 mg) and carbontetrabromide (215 mg) in dichloromethane (4 mL), andthe mixture was stirred for an hour at ambient temperature. Afterevaporation of the solvent, the residue was subjected to a silica gelcolumn chromatography eluting with a mixture of chloroform and ethylacetate (9:1) to give(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(161 mg) as a solid substance.

[0831] NMR (DMSO-d₆, δ):1.25 (3H, d, J=7 Hz), 3.67 (2H, m), 3.72 (3H,s), 3.74 (3H, s), 4.04 (1H, m), 4.36 (2H, d, J=6 Hz), 6.82-6.95 (4H, m),7.65 (1H, dd, J=2, 9 Hz), 8.07 (1H, d, J=2 Hz), 8.79 (1H, d, J=8 Hz),9.04 (1H, t, J=6 Hz).

EXAMPLE 88(5)

[0832] To a solution of(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(117 mg) in dimethylsulfoxide (2 mL) was added sodium cyamide (26.5 mg),and the mixture was stirred for an hour at 90° C. The resulting mixturewas diluted with ethyl acetate and washed successively with water andbrine. The organic layer was dried over sodium sulfate and evaporated invacuo. The residue was subjected to a silica gel column chromatographyeluting with a mixture of chloroform and ethyl acetate (9:1) to give(S)-5-cyano-2-(2-cyano-1-methylethylamino)-N-(3,4-dimethoxybenzyl)benzamide(73 mg) as a solid substance.

[0833] NMR (DMSO-d₆, δ): 1.29 (3H, d, J=7 Hz), 2.83 (2H, d, J=5 Hz),3.72 (3H, s), 3.74 (3H, s), 4.08 (1H, m), 4.36 (2H, d, J=6 Hz),6.82-6.95 (4H, m), 7.66 (1H, dd, J=2, 9 Hz), 8.09 (1H, d, J=2 Hz), 8.78(1H, d, J=8 Hz), 9.07 (1H, t, J=6 Hz)

[0834] Mass m/z: 377 (M⁺−1).

EXAMPLE 88(6)

[0835] To a solution of(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(61 mg) in dimethylsulfoxide (2 mL) was added imidazole (28.8 mg), andthe mixture was stirred for 2 hours at 100° C. The resulting mixture wasdiluted with ethyl acetate and washed successively with sodiumbicarbonate solution, water and brine. The organic layer was dried oversodium sulfate and evaporated in vacuo. The residue was subjected to asilica gel column chromatography eluting with 10% methanol inchloroform. The obtained product was treated with hydrochloric acid togive(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(1-imidazolyl)-1-methylethylamino]benzamidehydrochloride (24 mg) as a solid substance.

[0836] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 3.73 (3H, s), 3.75 (3H,s), 4.20-4.45 (5H, m), 6.80-6.97 (4H, m), 7.61 (1H, dd, J=2, 9 Hz), 7.64(1H, s), 7.72 (1H, s), 8.08 (1H, d, J=2 Hz), 8.63 (1H, d, J=8 Hz), 9.09(2H, m)

[0837] Mass m/z: 454 (M⁺−1).

EXAMPLE 88(7)

[0838](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[2-(2-methylimidazol-1-yl)-1-methylethylamino)benzamidehydrochloride (68 mg) was obtained from(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (153 mg) and 2-methylimidazole (87.1 mg) ina manner similar to Example 88 (6).

[0839] NMR (DMSO-d₆, δ): 1.23 (3H, d, J=7 Hz), 3.70 (1H, m), 3.73 (3H,s), 3.75 (3H, s), 4.29 (2H, m), 4.36 (1H, d, J=6 Hz), 6.70-6.95 (4H, m),7.49 (1H, d, J=2 Hz), 7.56 (1H, dd, J=2, 9 Hz), 7.62 (1H, d, J=2 Hz),8.04 (1H, d, J=2 Hz), 8.57 (1H, d, J=8 Hz), 9.11 (1H, t, J=6 Hz) Massm/z 468 (M⁺+1).

EXAMPLE 88(8)

[0840] To a solution of(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(147 mg) in dimethylsulfoxide (2 mL) was added benzenesulfinic acidsodium salt (81.6 mg), and the mixture was stirred for 3 hours at 90° C.The resulting mixture was diluted with ethyl acetate and washedsuccessively with water and brine. The organic layer was dried oversodium sulfate and evaporated in vacuo. The residue was subjected to asilica gel column chromatography eluting with a mixture of chloroformand ethyl acetate (9:1) to give(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-phenylsulfonyl-1-methylethylamino)benzamide(94 mg) as a solid substance.

[0841] NMR (DMSO-d₆, δ): 1.27 (3H, d, J=7 Hz), 3.65 (2H, m), 3.72 (3H,s), 3.74 (3H, s), 4.07 (1H, m), 4.30 (2H, m), 6.62 (1H, d, J=9 Hz), 6.83(1H, dd, J=2, 9 Hz), 6.91 (1H, d, J=9 Hz), 6.92 (1H, d, J=2 Hz),7.48-7.69 (4H, m), 7.79 (1H, d, J=8 Hz), 7.99 (1H, d, J=2 Hz), 8.55 (1H,d, J=8 Hz), 8.93 (1H, t, J=6 Hz)

[0842] Mass m/z: 492 (M⁺−1).

EXAMPLE 88(9)

[0843] To a solution of(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(101 mg) in a mixture of dimethylformamide (1.5 mL) and water (0.2 mL)was added sodium azide (45.6 mg), and the mixture was stirred for 2hours at 80° C. The resulting mixture was diluted with ethyl acetate andwashed successively with water and brine. The organic layer was driedover sodium sulfate and evaporated in vacuo The residue was trituratedwith diethyl ether to give(S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(75 mg) as a solid substance.

[0844] NMR (DMSO-d₆, δ): 1.18 (3H, d, J=7 Hz), 3.49 (2H, m), 3.72 (3H,s), 3.74 (3H, s), 3.96 (1H, m), 4.36 (2H, d, J=6 Hz), 6.81-6.95 (4H, m),7.64 (1H, dd, J=2, 9 Hz), 8.07 (1H, d, J=2 Hz), 8.74 (1H, d, J=8 Hz),9.03 (1H, t, J=6 Hz)

[0845] Mass m/z: 393 (M⁺−1).

EXAMPLE 88(10)

[0846] To a solution of(S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(505 mg) in a mixture of ethanol (5 mL) and dichloromethane (3 mL) wasadded 10% palladium on activated carbon (60 mg), and the mixture wasstirred under hydrogen atmosphere (1 atm) for 3 hours at ambienttemperature. The resulting mixture was filtered through celite andwashed with ethanol. The filtrate and the washings were combined andevaporated in vacuo. The residue was subjected to a silica gel columnchromatography eluting with 10% methanol in chloroform to give(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(393 mg) as a solid substance.

[0847] NMR (DMSO-d₆, δ): 1.13 (3H, d, J=7 Hz), 1.58 (2H, br), 2.55 (1H,m), 2.57 (1H, m), 3.54 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d,J=6 Hz), 6.81-6.95 (4H, m), 7.59 (1H, dd, J=2, 9 Hz), 8.02 (1H, d,J=2H), 8.66 (1H, d, J=8 Hz), 8.98 (1H, t, J=6 Hz)

[0848] Mass m/z: 367 (M⁺−1).

EXAMPLE 88(11)

[0849](S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[2-(formamido)-1-methylethylamino]benzamide(73 mg) was obtained from(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(100 mg) and ethyl formate (2.0 g) in a manner similar to Example 73(2).

[0850] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=7 Hz), 3.05 (1H, m), 3.28 (1H,m), 3.70 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d, J=6 Hz),6.81-6.98 4H, m), 7.63 (1H, dd, J=2, 9 Hz), 8.03-8.07 (2H, m), 8.26 (1H,m), 8.63 (1H, d, J=8 Hz), 9.01 (1H, t, J=6 Hz).

[0851] Mass m/z: 395 (M⁺−1).

EXAMPLE 88(12)

[0852] To a solution of(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(99 mg) in dichloromethane (3 mL) was added acetic anhydride (38 mg),and the mixture was stirred for an hour at ambient temperature. Theresulting mixture was evaporated in vacuo. The residue was trituratedwith diisopropyl ether to give(S)-2-[2-(acetamido)-1-methylethylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(107 mg) as a solid substance.

[0853] NMR (DMSO-d₆, δ): 1.15 (3H, d, J=7 Hz), 1.80 (3H, s), 3.04 (1H,m), 3.23 (1H, m), 3.68 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d,J=6 Hz), 6.81-7.02 (4H, m), 7.63 (1H, dd, J=2, 9 Hz), 8.05 (1H, d, J=8Hz), 8.10 (1H, t, J=6 Hz), 8.59 (1H, d, J=8 Hz), 9.01 (1H, t, J=6 Hz)

[0854] Mass m/z: 409 (M⁺−1).

EXAMPLE 88(13)

[0855] To a mixture of(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(98 mg) and triethylamine (0.074 mL) in dichloromethane (3 mL) was addedmethanesulfonyl chloride (0.029 mL), and the mixture was stirred for anhour at ambient temperature. The resulting mixture was diluted withethyl acetate and washed successively with water and brine. The organiclayer was dried over sodium sulfate and evaporated in vacuo. The residuewas triturated with diisopropyl ether to give(S)—S-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(methanesulfonylamino)-1-methylethylaminojbenzamide(110 mg) as a solid substance.

[0856] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=7 Hz), 2.88 (3H, s), 2.94 (1H,m), 3.07 (1H, m), 3.68 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d,J=6 Hz), 6.81-6.94 (4H, m), 7.27 (1H, t, J=6 Hz), 7.64 (1H, dd, J=2, 9Hz), 8.05 (1H, d, J=8 Hz), 8.63 (1H, d, J=8 Hz), 9.02 (1H, t, J=6 Hz)

[0857] Mass m/z: 445 (M⁺−1).

EXAMPLE 88(14)

[0858](S)-5-Cyano-2-[2-(ethoxycarbonylamino)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide(60 mg) was obtained from(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)-benzamide(110 mg) and ethyl chloroformate (0.04 mL) in a manner similar toExample 88(13).

[0859] NMR (DMSO-d₆, δ): 1.14 (3H, t, J=7 Hz), 1.15 (3H, d, J=7 Hz),2.87 (1H, m), 3.15 (1H, m), 3.67 (1H, m), 3.72 (3H, s), 3.74 (3H, s),3.98 (2H, q, J=7 Hz), 4.35 (2H, d, J=6 Hz), 6.82-6.99 (4H, m), 7.37 (1H,t, J=6 Hz), 7.63 (1H, dd, J=2, 9 Hz), 8.05 (1H, d, J=8 Hz), 8.59 (1H, d,J=8 Hz), 9.00 (1H, t, J=6 Hz)

[0860] Mass m/z : 439 (M⁺−1).

EXAMPLE 88(15)

[0861] To a solution of(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide(52 mg) in ethanol (3 mL) was added dimethyl N-cyanodithioiminocarbonate(22.7 mg), and the mixture was stirred for 6 hours at ambienttemperature. The solvent of the reaction mixture was evaporated invacuo. The residue was subjected to a silica gel column chromatographyeluting with a mixture of chloroform and ethyl acetate (2:1) to give(S)-5-cyano-2-[2-(N-cyano-S-methylisothioureido)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide(52 mg) as a solid substance.

[0862] NMR (DMSO-d₆, δ): 1.18 (3H, d, J=7 Hz), 3.29 (1H, m), 3.34 (3H,s), 3.44 (1H, m), 3.72 (3H, s), 3.75 (3H, s), 3.93 (1H, m), 4.36 (2H,m), 6.81-6.97 (4H, m), 7.62 (1H, dd, J=2, 9 Hz), 8.06 (1H, d, J=8 Hz),8.49 (1H, br), 8.64 (1H, d, J=8 Hz), 9.02 (1H, t, J=6H)

[0863] Mass m/z: 465 (M⁺−1).

EXAMPLE 88(16)

[0864] To a solution of(S)-5-cyano-2-[2-(N-cyano-S-methylisothioureido)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide(48 mg) in ethanol (2 mL) was added methylamine in methanol (30%, 0.3mL), and the mixture was stirred in a sealed tube for 6 hours at 60° C.The resulting mixture was evaporated in vacuo and the residue wastriturated with diethyl ether to give(S)-5-cyano-2-[2-(2-cyano-3-methylguanidino)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide(32 mg) as a solid substance.

[0865] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=7 Hz), 2.63 (3H, d, J=5 Hz),3.07 (1H, m), 3.27 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 3.83 (1H, m),4.35 (2H, m), 6.82-7.00 (4H, m), 7.07 (1H, q, J=5 Hz), 7.14 (1H, t, J=5Hz), 7.60 (1H, dd, J=2, 9 Hz), 8.05 (1H, d, J=8 Hz), 8.59 (1H, d, J=8Hz), 9.02 (1H, t, J=6 Hz)

[0866] Mass m/z: 448 (M⁺−1).

EXAMPLE 88(17)

[0867](R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide(103 mg) was prepared from5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzainide (115 mg) and(R)-2-amino-1-propanol (0.085 mL) in a similar manner to Example 1(1).

[0868] NMR (DMSO-d₆, δ): 1.13 (3H, d, J=6 Hz), 3.42 (2H, t, J=5 Hz),3.67 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.34 (2H, d, J=5 Hz), 4.92(1H, t, J=5 Hz), 6.81-6.95 (4H, in), 7.60 (1H, dd, J=2, 9 Hz), 8.03 (1H,d, J=2 Hz), 8.69 (1H, d, J=8 Hz), 8.97 (1H, t, J=5 Hz)

[0869] Mass m/z: 368 (M⁺−1).

[0870] Preparation 89(1)

[0871] 5-Bromo-N-(3,4-dirnethoxybenzyl)-2-fluorobenzamide (4.01 g) wasobtained from 5-bromo-2-fluorobenzoic acid (3.0 g) and veratrylamine(2.27 mL) in a in a manner similar to Preparation 1.

[0872] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.74 (3H, s), 4.38 (2H, d, J=6Hz), 6.82-6.96 (3H, m), 7.31 (1H, t, J=9 Hz), 7.68-7.76 (2H, m), 8.94(1H, t, J=6 Hz)

[0873] Mass m/z: 366, 368 (M⁺−1).

[0874] Preparation 89(2)

[0875] To a solution of5-bromo-N-(3,4-dinethoxybenzyl)-2-fluorobenzamide (200 mg) indimethylformamide (2 mL) were added methyl acrylate (0.068 mL),triethylamine (0.09 mL) and dichlorobis(triphenylphosphine)palladium(II)(13.4 mg), and the mixture was stirred for 6 hours at 120° C. in asealed tube. The resulting mixture was diluted with ethyl acetate andwashed successively with water and brine. The organic layer was driedover sodium sulfate and evaporated in vacuo. The residue was subjectedto a silica gel column chromatography eluting with a mixture ofchloroform and ethyl acetate (9:1) to giveN-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2-(methoxycarbonyl)ethenyl]benzamide(117 mg) as a solid substance.

[0876] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.74 (3H, s), 3.75 (3H, s), 4.40(2H, d, J=6 Hz), 6.68 (1H, d, J=16 Hz), 6.82-6.96 (3H, in), 7.36 (1H, t,J=9 Hz), 7.70 (1H, d, J=16 Hz), 7.87-7.96 (2H, m), 8.91 (1H, t, J=6 Hz).

[0877] Mass m/z : 372 (M⁺+1).

EXAMPLE 89(1)

[0878]N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(trans-2-methoxycarbonylethenyl)benzamide(121 mg) was obtained fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2-(methoxycarbonyl)ethenyl]benzamide and trans-4-aminocyclohexanol (118 mg) in a mannersimilar to Example 1 (1).

[0879] NMR (DMSO-d₆, δ): 1.14-1.40 (4H, m), 1.76-1.86 (2H, m), 1.91-2.00(2H, m), 3.35-3.53 (2H, m), 3.68 (3H, s), 3.72 (3H, s), 3.74 (3H, s),4.37 (2H, d, J=6 Hz), 4.59 (1H, d, J=4 Hz), 6.41 (1H, d, J=16 Hz), 6.77(1H, d, J=9 Hz), 6.83 (1H, dd, J=2, 9 Hz), 6.91 (1H, d, J=9 Hz), 6.93(1H, d, J=2 Hz), 7.52 (1H, d, J=16 Hz), 7.61 (1H, dd, J=2, 9 Hz), 8.02(1H, d, J=2 Hz), 8.49 (1H, d, J=8 Hz), 8.91 (1H, t, J=6 Hz).

EXAMPLE 89(2)

[0880] To a solution ofN-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(trans-2-methoxycarbonylethenyl)benzamide(82 mg) in a mixture of tetrahydrofuran (2 mL) and water (0.1 mL) wereadded 4-methylmorpholine N-oxide (53.2 mg) and 4% aqueous solution ofosmium tetroxide (0.1 mL). The mixture was stirred for 2 hours underreflux. To the mixture were added 50% aqueous methanol (2 mL) and sodiumperiodate (161 mg). After siring for 20 minutes, the mixture was dilutedwith ethyl acetate and washed successively with water and brine. Theorganic layer was dried over sodium sulfate and evaporated in vacuo. Theresidue was subjected to a silica gel column chromatography eluting witha mixture of chloroform and ethyl acetate (1:1) to giveN-(3,4-dimethoxybenzyl)-5-formyl-2-(trans-4-hydroxycyclohexylamino)benzamide(117 mg) as a solid substance.

[0881] NMR (DMSO-d₆, δ): 1.16-1.42 (4H, m), 1.77-1.87 (2H, m), 1.92-2.02(2H, m), 3.38-3.54 (2H, m), 3.72 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6Hz), 4.61 (1H, d, J=4 Hz), 6.80-6.95 (4H, m), 7.75 (1H, dd, J=2, 9 Hz),8.17 (1H, d, J=2 Hz), 8.79 (1H, d, J=8 Hz), 9.10 (1H, t, J=6 Hz), 9.65(1H, s)

[0882] Mass m/z: 411 (M⁺−1).

[0883] Preparation 90(1)

[0884] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-formylbenzamide (915.8 mg) wasobtained from N-(3,4-dimethoxybenzyl)-2-fluoro-5-vinylbenzamide (1.1 g)in a manner similar to Example 89(2) as a colorless solid substance.

[0885] mp. 132-133° C.

[0886] NMR (CDCl₃, δ): 3.86 (3H, s), 3.89 (3H, s), 4.64 (2H, d, J=5.5Hz), 6.85 (1H, d, J=8.0 Hz), 6.91 (1H, s), 6.92 (1H, d, J=8.0 Hz),6.89-7.01 (1H, m), 7.29 (1H, dd, J=11.0, 8.5 Hz), 8.06 (1H, m), 8.66(1H, dd, J=7.0, 2.0 Hz), 10.04 (1H, s)

[0887] Mass m/z: 316 (M⁺−1).

[0888] Preparation 90(2)

[0889] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-formylbenzamide (900 mg) andglyoxal trimeric dihydrate (596 mg) were stirred in methanol (9 mL) at−10° C. Ammonia was bubbled through the solution for 5 minutes and themixture was stirred for an hour at −10° C. The mixture was allowed towarm to ambient temperature over 16 hours, then poured into water andextracted twice with chloroform. The combined extracts were dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue waspurified by a flash column chromatography over silica gel with 5%methanol in chloroform as eluent to giveN-(3,4-dimethoxybenzyl)-2-fluoro-5-(1H-imidazol-2-yl)benzamide (323. 1mg) as a pale brown solid substance.

[0890] mp. 164-166° C.

[0891] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.75 (3H, s), 4.42 (2H, d, J=5.5Hz), 6.87 (1H, d, J=8.0 Hz), 6.93 (1H, d, J=8.0 Hz), 6.98 (1H, s), 7.03(1H, s), 7.26 (1H, s), 7.39 (1H, t, J=8.0 Hz), 8.05 (1H, m), 8.17 (1H,dd, J=7.0, 1.5 Hz), 8.92 (1H, t, J=5.5 Hz), 12.61 (1H, s)

[0892] Mass m/z: 354 (M⁺−1).

EXAMPLE 90

[0893]N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(1H-imidazol-2-yl)benzamide(18.5 mg) was obtained as a pale gray solid substance fromN-(3,4-dimethoxybenzyl)-2-fluoro-5-(1H-imidazol-2-yl)benzamide (70 mg)and trans-4-aminocyclohexanol (90.8 mg) in a manner similar to Example1(1).

[0894] mp. 189-190° C.

[0895] NMR (DMSO-d₆, δ): 1.10-1.42 (4H, m), 1.76-1.88 (2H, m), 1.93-2.05(2H, m), 3.27-3.54 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, d,J=5.5 Hz), 4.58 (1H, d, J=4.5 Hz), 6.80 (1H, d, J=8.5 Hz), 6.85 (1H, d,J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 6.97 (1H, s), 7.04 (2H, s), 7.77 (2H,d, J=8.0 Hz), 8.13 (1H, s), 8.83 (1H, t, J=5.5 Hz), 12.18 (1H, s)

[0896] Mass m/z 451 (M⁺+1).

[0897] Preparation 91(1)

[0898] To a solution of 2-chloro-5-methylphenol (5.00 g) and potassiumcarbonate (7.27 g) in anhydrous dimethylformamide (30 mL) was addedmethyl iodide (3.27 mL), and the mixture was stirred for 3 hours atambient temperature. The mixture was partitioned between water and ethylacetate. The separated organic layer was washed with water and brine anddried over magnesium sulfate. The resultant was evaporated in vacuo togive 4-chloro-3-methoxytoluene as a colorless oil (5.65 g).

[0899] NMR (CDCl₃, δ): 2.34 (3H, s), 3.89 (3H, s), 6.72 (2H, m), 7.22(1H, d, J=8 Hz).

[0900] Preparation 91(2)

[0901] To a solution of 4-chloro-3-methoxytoluene (5.65 g) andN-bromosuccinimide (6.74 g) in anhydrous dichloromethane (60 mL) wasadded 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (674 mg). Afterstirring for 3 hours under reflux, the mixture was washed with water andbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas triturated with hexane to give 4-chloro-3-methoxybenzyl bromide aswhite powders (2.00 g).

[0902] NMR (CDCl₃, δ): 3.92 (3H, s), 4.46 (2H, s), 6.91-6.96 (2H, m),7.32 (1H, d, J=8 Hz).

[0903] Preparation 91(3)

[0904] To a solution of 4-chloro-3-methoxybenzyl bromide (7.00 g) inanhydrous dimethylformamide (50 mL) was added potassium phthalimide(6.03 g), and the mixture was stirred for 2 hours at ambienttemperature. The mixture was partitioned between ethyl acetate andwater. The separated organic layer was washed with water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether to giveN-(4-chloro-3-methoxybenzyl)phthalimide as white powders (5.88 g).

[0905] NMR (CDCl₃, δ): 3.90 (3H, s), 4.80 (2H, s), 6.96 (1H, d, J=8 Hz),7.05 (1H, s), 7.25-7.31 (1H, m), 7.68-7.75 (2H, m), 7.82-7.90 (2H, m).Preparation 91(4) To a solution ofN-(4-chloro-3-methoxybenzyl)phthalimide (3.00 g) in ethanol (60 mL) wasadded hydrazine hydrate (2.62 mL), and the mixture was heated for anhour under reflux. The resulting precipitates were filtered off and thefiltrate was evaporated in vacuo. The residue was partitioned betweenchloroform and an aqueous saturated sodium bicarbonate solution. Theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo to give4-chloro-3-methoxybenzylamine as a yellow oil (1.64 g).

[0906] NMR (CDCl₃, δ): 3.86 (2H, s), 3.92 (3H, s), 6.85 (1H, d, J=8 Hz),6.93 (1H, s), 7.25-7.34 (1H, d, J=8 Hz).

[0907] Preparation 91(5)

[0908] N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (1.97 g)was obtained from 2-fluoro5-nitrobenzoic acid (1.72 g) and4-chloro-3-methoxybenzylamine (1.64 g) in a manner similar toPreparation 55.

[0909] NMR (CDCl₃, δ): 3.85 (3H, s), 4.50 (2H, d, J=7 Hz), 6.94 (1H, d,J=8 Hz), 7.15 (1H, s), 7.39 (1H, d, J=8 Hz), 7.64 (1H, m), 8.40-8.47(2H, m), 9.21 (1H, br)

[0910] Mass m/z: 337 (M⁺).

EXAMPLE 91

[0911]N-(4-Chloro-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylamino]-5-nitrobenzamide(165 mg) was obtained fromN-(4-chloro-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and2-amino-1,3-propanediol (60.5 mg) in a manner similar to Example 1(1).

[0912] mp: 176-177° C.

[0913] NMR (DMSO-d₆, δ): 3.50 (4H, br), 3.55-3.68 (1H, br), 3.82 (3H,s), 4.40 (2H, d, J=7 Hz), 4.90 (2H, t, J=7 Hz), 6.86-6.93 (2H, m), 7.11(1H, s), 7.35 (1H, d, J=8 Hz), 8.10 (1H, dd, J=4, 8 Hz), 8.58 (1H, d,J=4 Hz), 9.19 (1H, d, J=8 Hz), 9.32 (1H, br)

[0914] Mass m/z 408 (M⁺).

[0915] Preparation 92(1)

[0916] To a mixture of 4-(methylthio)benzyl alcohol (2.00 g) and carbontetrabromide (6.45 g) in dichloromethane (40 mL) was addedtriphenylphosphine (4.08 g), and the mixture was stirred for an hour atambient temperature. After evaporation of the solvent, the residue waspurified by a silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (20:1) to give 4-(methylthio)benzyl bromide(2.00 g) as a colorless oil.

[0917] NMR (CDCl₃, δ): 2.49 (3H, s), 4.48 (2H, s), 7.20 (2H, d, J=8 Hz),7.32 (2H, d, J=8 Hz).

[0918] Preparation 92(3)

[0919] N-[4-(Methylthio)benzyl]phthalimide (2.40 g) was obtained ascolorless powders from 4-(methylthio)benzyl bromide (1.99 g) andpotassium phthalimide (1.87 g) in a manner similar to Preparation 91(3).

[0920] NMR (CDCl₃, δ): 2.45 (3H, s), 4.80 (2H, s), 7.19 (2H, d, J=8 Hz),7.36 (2H, d, J=8 Hz), 7.69 (2H, m), 7.84 (2H, m). Prepation 92(3)4-(Methylthio)benzylamine (1. 17 g) was obtained as a pale yellow oilfrom N-[4-(methylthio)benzyl]phthalimide (2.04 g) in a manner similar toPreparation 91(4).

[0921] NMR (CDCl₃, δ); 2.48 (3H, s), 3.83 (2H, s), 7.24 (4H, s).Preparation 92(4) 2-Fluoro-N-[4-(methylthio)benzyl]-5-nitrobenzamide(1.45 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoicacid (1.35 g) and 4-(methylthio)benzylamine (1.15 g) in a manner similarto

[0922] Preparation 55.

[0923] NMR (CDCl₃, δ): 3.89 (6H, s), 4.63 (2H, d, J=7 Hz), 6.84-6.93(4H, m), 7.30 (1H, m), 8.35 (1H, m), 9.03 (1H, m)

[0924] Mass m/z: 333 (M⁺).

EXAMPLE 92

[0925] 2-(trans-4-Hydroxycyclohexyl)amino-N-14-(methylthio)benzyl]-5-nitrobenzamide (456 mg) was obtained asyellow powders from 2-fluoro-N-[4-(methylthio)benzyl]-5-nitrobenzamide(400 mg) and trans4-aminocyclohexanol (288 mg) in a manner similar toExample 1(1).

[0926] NMR (DMSO-d₆, δ): 1.20-1.44 (4H, br), 1.75-1.88 (2H, br),1.90-2.05 (2H, br), 2.45 (3H, s), 3.42-3.59 (2H, br), 4.39 (2H, d, J=7Hz), 4.61 (1H, d, J=4 Hz), 6.91 (1H, d, J=8 Hz), 7.20-7.30 (4H, m), 8.11(1H, dd, J=4, 8 Hz), 8.62 (1H, d, J=4 Hz), 9.10 (1H, d, J=8 Hz), 9.38(1H, br)

[0927] Mass m/z: 414 (M⁺).

[0928] Preparation 93(1)

[0929] 3,5-Dichloro-4-methoxytoluene (5.39 g) was obtained as yellow oilfrom 2,6-dichloro-4-methylphenol (5.00 g) and methyl iodide (2.64 mL) ina manner similar to preparation 91(1).

[0930] NMR (CDCl₃, δ): 2.27 (3H, s), 3.87 (3H, s), 7.10 (2H, s).

[0931] Preparation 93(2)

[0932] 3,5-Dichloro-4-methoxybenzyl bromide (9.10 g) was obtained asyellow oil from 3,5-dichloro-4-methoxytoluene (5.39 g) in a mannersimilar to preparation 91(2).

[0933] NMR (CDCl₃, δ): 3.90 (3H, s), 4.36 (2H, s), 7.33 (2H, s).

[0934] Preparation 93(3)

[0935] N-(3,5-Dichloro-4-methoxybenzyl)phthalimide (6.34 g) was obtainedas colorless powders from 3,5-dichloro-4-methoxybenzyl bromide (8.00 g)and potassium phthalimide (6.04 g) in a manner similar to Preparation91(3).

[0936] NMR (CDCl₃, δ): 3.86 (3H, s), 4.74 (2H, s), 7.37 (2H, s),7.70-7.78 (2H, m), 7.83-7.90 (2H, m).

[0937] Preparation 93(4)

[0938] 3,5-Dichloro-4-methoxybenzylamine (1.50 g) was obtained as yellowoil from N-(3,5-dichloro-4-methoxybenzyl)phthaliride (3.00 g) in amanner similar to Preparation 91(4).

[0939] NMR (CDCl₃, δ): 3.82 (2H, s), 3.90 (3H, s), 7.28 (2H, br).

[0940] Preparation 93(5)

[0941] N-(3,5-Dichloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (2.20g) was obtained as colorless powders from 2-fluoro-5-nitrobenzoic acid(1.31 g) and 3,5-dichloro-4-methoxybenzylamine (1.50 g) in a mannersimilar to Preparation 55.

[0942] NMR (DMSO-d₆, δ): 3.81 (3H, s), 4.46 (2H, d, J=7 Hz), 7.48 (2H,s), 7.66 (1H, t, J=8 Hz), 8.38-8.45 (1H, m), 8.46-8.53 (1H, m), 9.20(1H, br).

EXAMPLE 93

[0943]N-(3,5-Dichloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(365 mg) was obtained as yellow powders fromN-(3,5-dichloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (400 mg) andtrans-4-aminocyclohexanol (185 mg) in a manner similar to Example 1(1).

[0944] NMR (DMSO-d₆, δ): 1.20-1.43 (4H, m), 1.76-1.89 (2H, br), 1.91-2.01 (2H, br), 3.48 (2H, br), 3.81 (3H, s), 4.39 (2H, d, J=7 Hz), 4.61(1H, d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.45 (2H, s), 8.12 (1H, dd, J=4,8 Hz), 8.63 (1H, d, J=4 Hz), 9.03 (1H, d, J=8 Hz), 9.37 (1H, br).

[0945] Preparation 94(1)

[0946] 4-Chloro-3-nitrobenzyl bromide (7.90 g) was obtained as orangeoil from 4-chloro-3-nitrotoluene (5.00 g) in a manner similar to

[0947] Preparation 91(2).

[0948] NMR (CDCl₃, δ): 4.47 (2H, s), 7.54 (2H, s), 7.92 (1H, s).Preparation 94(2) N-(4-Chloro-3-nitrobenzyl)phthalimide (5.49 g) wasobtained as colorless powders from 4-chloro-3-nitrobenzyl bromide (7.00g) and potassium pbthalimide (5.69 g) in a manner similar to Preparation91(3).

[0949] NMR (CDCl₃, δ): 4.88 (2H, s), 7.50 (1H, d, J=8 Hz), 7.60 (1H, dd,J=4, 8 Hz), 7.75 (2H, m), 7.88 (2H, m), 7.90 (1H, d, J=4 Hz).

[0950] Preparation 94(3)

[0951] 4-Chloro-3-nitrobenzylamine (1.27 g) was obtained as brown oilfrom N-(4-chloro-3-nitrobenzyl)phthalimide (3.00 g) in a manner similarto Preparation 91(4).

[0952] NMR (CDCl₃, δ): 3.96 (2H, s), 7.50 (2H, s), 7.89 (1H, s).

[0953] Preparation 94(4)

[0954] N-(4-Chloro-3-nitrobenzyl)-2-fluoro-5-nitrobenzamide (1.72 g) wasobtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1.20g) and 4-chloro-3-nitrobenzylamine(1.25 g) in a manner similar toPreparation 55.

[0955] NMR (DMSO-d₆, δ): 4.58 (2H, d, J=7 Hz), 7.62-7.73 (2H, m), 7.78(1H, d, J=8 Hz), 8.06 (1H, s), 8.44 (1H, m), 8.50 (1H, m), 9.29 (1H, br)

[0956] Mass m/z: 352 (M⁺).

EXAMPLE 94

[0957](R)-N-(4-Chloro-3-nitrobenzyl)-2-[1-(hydroxymethyl)propylamino]-5-nitrobenzamide(150 mg) was obtained as yellow powders fromN-(4-chloro-3-nitrobenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and(R)-2-amino-1-butanol (56.7 mg) in a manner similar to Example 1(1).

[0958] NMR (DMSO-d₆, δ): 0.89 (3H, t, J=7 Hz), 1.40-1.56 (1H, m),1.60-1.77 (1H, m), 3.47 (2H, br), 3.60 (1H, br), 4.51 (2H, d, J=7 Hz),4.91 (1H, t, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.67 (1H, dd, J=4, 8 Hz),7.76 (1H, d, J=8 Hz), 8.04 (1H, d, J=4 Hz), 8.12 (1H, dd, J=4, 8 Hz),8.65 (1H, d, J=4 Hz), 9.14 (1H, d, J=8 Hz), 9.46 (1H, br)

[0959] Mass m/z: 421 (M⁺).

[0960] Preparation 95(1)

[0961] To a mixture of 4-cyanobenzaldehyde (5.00 g) in ethanol (50 mL)and tetrahydrofuran (20 mL) was added sodium borohydride (2.16 g) underice-water cooling, and the mixture was stirred for an hour at 0° C.After evaporation of the solvent, the residue was partitioned betweenethyl acetate and water. The separated organic layer was washed withwater and brine, dried over magnesium sulfate and evaporated in vacuo togive 4-cyanobenzyl alcohol (4.76 g) as a colorless oil.

[0962] NMR (CDCl₃, δ): 1.98 (1H, t, J=7 Hz), 4.78 (2H, d, J=7 Hz), 7.48(2H, d, J=8 Hz), 7.66 (2H, d, J=8 Hz).

[0963] Preparation 95(2)

[0964] 4-Cyanobenzyl bromide (3.16 g) was obtained as colorless powdersfrom 4-cyanobenzyl alcohol (2.35 g) in a manner similar to Preparation92(1).

[0965] NMR (CDCl₃, δ): 4.48 (2H, s), 7.50 (2H, d, J=8 Hz), 7.64 (2H, d,J=8 Hz).

[0966] Preparation 95(3)

[0967] N-(4-Cyanobenzyl)phthalimide (3.75 g) was obtained as colorlesspowders from 4-cyanobenzyl bromide (3.00 g) and potassium phthalimide(3.12 g) in a manner similar to Preparation 91(3).

[0968] NMR (CDCl₃, δ): 4.89 (2H, s), 7.52 (2H, d, J=8 Hz), 7.63 (2H, d,J=8 Hz), 7.75 (2H, m), 7.86 (2H, m).

[0969] Preparation 95(4)

[0970] 4-Cyanobenzylamine (1.61 g) was obtained as pale yellow oil fromN-(4-cyanobenzyl)phthalimide (3.70 g) in a manner similar to Preparation91(4).

[0971] NMR (CDCl₃, δ): 3.96 (2H, s), 7.45 (2H, d, J=8 Hz), 7.63 (2H, d.J=8 Hz).

[0972] Preparation 95(5)

[0973] N-(4-Cyanobenzyl)-2-fluoro-5-nitrobenzamide (3.07 g) was obtainedas colorless powders from 2-fluoro-5-nitrobenzoic acid (2.19 g) and4-cyanobenzylamine (1.61 g) in a manner similar to Preparation 55.

[0974] NMR (DMSO-d₆, δ): 4.58 (2H, d, J=7 Hz), 7.55 (2H, d, J=8 Hz),7.65 (1H, t, J=7 Hz), 7.84 (2H, d, J=8 Hz), 8.39-8.51 (2H, m), 9.29 (1H,br)

[0975] Mass m/z: 298 (M⁺).

EXAMPLE 95

[0976]N-(4-Cyanobenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(428 mg) was obtained as yellow powders fromN-(4-cyanobenzyl)-2-fluoro-5-nitrobenzamide (400 mg) andtrans4-aminocyclohexanol (308 mg) in a manner similar to Example 1(1).

[0977] NMR (DMSO-d₆, δ): 1.18-1.45 (4H, br), 1.75-1.88 (2H, br),1.90-2.00 (2H, br), 3.40-3.58 (2H, br), 4.50 (2H, d, J=7 Hz), 4.62 (1H,d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.51 (2H, d, J=8 Hz), 7.82 (2H, d, J=8Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.67 (1H, d, J=4 Hz), 9.07 (1H, d, J=8Hz), 9.50 (1H, br)

[0978] Mass m/z: 393 (M⁺).

[0979] Preparation 96

[0980]2-Fluoro-5-nitro-N-(2-pyridylmethyl)benzamide (468 mg) wasobtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg)and 2-(aminomethyl)pyridine (307 mg) in a manner similar to Preparation55.

[0981] NMR (DMSO-d₆, δ): 4.60 (2H, d, J=5 Hz), 7.30 (1H, t, J=5 Hz),7.40 (1H, d, J=8 Hz), 7.66 (1H, t, J=8 Hz), 7.80 (1H, t, J=7.5 Hz),8.39-8.49 (1H, m), 8.49-8.57 (2H, m), 9.24 (1H, br)

[0982] Mass m/z: 276.1 (M⁺+1).

EXAMPLE 96

[0983]2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(2-pyridylmethyl)benzamide(580 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(2-pyridylmethyl)benzamide (450 mg) andtrans4-aminocyclohexanol (282 mg) in a manner similar to Example 1(1).

[0984] NMR (DMSO-d₆, δ): 1.18-1.43 (4H, m), 1.70-1.88 (2H, m), 1.88-2.04(2H, m), 3.38-3.59 (2H, m), 4.54 (2H, d, J=5 Hz), 4.61 (1H, d, J=4 Hz),6.92 (1H, d, J=8 Hz), 7.28 (1H, dd, J=5, 7.5 Hz), 7.33 (1H, d, J=8 Hz),7.77 (1H, td, J=8, 2 Hz), 8.12 (1H, dd, J=8, 2 Hz), 8.51 (1H, d, J=5Hz), 8.68 (1H, d, J=2 Hz), 9.05 (1H, d, J=8 Hz), 9.48 (1H, m)

[0985] Mass m/z: 369.2 (M⁺−1).

[0986] Preparation 97

[0987] 2-Fluoro-5-nitro-N-(3-pyridylmethyl)benzamide (510 mg) wasobtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg)and 3-(aminomethyl)pyridine (307 mg) in a manner similar to

[0988] Preparation 55.

[0989] NMR (DMSO-d₆, δ): 4.52 (2H, d, J=5 Hz), 7.40 (1H, dd, J=5, 7.5Hz), 7.64 (1H, t, J=8 Hz), 7.76 (1H, d, J=7.5 Hz), 8.36-8.51 (3H, m),8.59 (1H, d, J=2 Hz), 9.25 (1H, br)

[0990] Mass m/z: 274.0 (M⁺−1).

EXAMPLE 97

[0991]2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(3-pyridylmethyl)benzamide(625 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(3-pyridylmethyl)benzamide (550 mg) andtrans4-aminocyclohexanol (345 mg) in a manner similar to Example 1(1).

[0992] NMR (DMSO-d₆, δ): 1.19-1.44 (4H, m), 1.71-1.88 (2H, m), 1.88-2.07(2H, m), 3.40-3.61 (2H, m), 4.45 (2H, d, J=5 Hz), 4.62 (1H, d, J=4 Hz),6.92 (1H, d, J=8 Hz), 7.37 (1H, dd, J=5, 7.5 Hz), 7.43 (1H, d, J=7.5Hz), 8.12 (1H, dd, J=8, 2 Hz), 8.47 (1H, d, J=5 Hz), 8.56 (1H, d, J=2Hz), 8.63 (1H, d, J=2 Hz), 9.06 (1H, d, J=8 Hz), 9.43 (1H, m)

[0993] Mass m/z: 369.3 (M⁺−1).

[0994] Preparation 98

[0995] 2-Fluoro-5-nitro-N-(4-pyridylmethyl)benzamide (534 mg) wasobtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg)and 4-(aminomethyl)pyridine (307 mg) in a manner similar to Preparation55.

[0996] NMR (DMSO-d₆, δ): 4.53 (2H, d, J=5 Hz), 7.35 (2H, d, J=5 Hz),7.66 (1H, t, J=8 Hz), 8.38-8.65 (4H, m), 9.28 (1H)

[0997] Mass m/z: 274.1 (M⁺−1).

EXAMPLE 98

[0998]2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(4-pyridylmethyl)benzamide(548 mg) was obtained as yellow powders from2-fluoro-5-nitro-N-(4-pyridylmethyl)benzamide (500 mg) andtrans4-aminocyclohexanol (314 mg) in a manner similar to Example 1(1).

[0999] NMR (DMSO-d₆, δ): 1.14-1.43 (4H, m), 1.69-1.88 (2H, m), 1.88-2.05(2H, m), 3.36-3.60 (2H, m), 4.45 (2H, d, J=5 Hz), 4.61 (1H, d, J=4 Hz),6.93 (1H, d, J=8 Hz), 7.31 (2H, d, J=5 Hz), 8.13 (1H, dd, J=8, 2 Hz),8.51 (2H, d, J=5 Hz), 8.69 (1H, d, J=2 Hz), 9.06 (1H, d, J=8 Hz), 9.48(1H, m)

[1000] Mass m/z: 369.2 (M⁺−1).

[1001] Preparation 99(1)

[1002] 2-Naphthalenemethylamine hydrochloride (1.36 g) was obtained aswhite powders from N-(2-naphthylmethyl)phthalimide (2.80 g) in a mannersimilar to Preparation 91(4).

[1003] NMR (DMSO-d₆, δ): 4.19 (2H, s), 7.51-7.60 (2H, m), 7.63 (1H, dd,J=8, 2 Hz), 7.87-8.05 (4H, m), 8.46 (3H, br).

[1004] Preparation 99(2)

[1005] 2-Fluoro-N-(2-naphthylmethyl)-5-nitrobenzamide (1.73 g) wasobtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g)and 2-naphthalenemethylamine hydrochloride (1.10 g) in a manner similarto Preparation 55.

[1006] NMR (DMSO-d₆, δ): 4.67 (2H, d, J=5 Hz), 7.44-7.57 (3H, m), 7.64(1H, t, J=8 Hz), 7.80-7.98 (4H, m), 8.37-8.47 (1H, m), 8.47-8.55 (1H,m), 9.28 (1H, m).

EXAMPLE 99

[1007] 2-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-N-(2-naphthylmethyl)-5-nitrobenzamide (156 mg) was obtainedas yellow powders from 2-fluoro-N-(2-naphthylmethyl)-5-nitrobenzamide(200 mg) and 2-amino-1,3-propanediol (84.3 mg) in a manner similar toExample 1(1).

[1008] NMR (DMSO-d₆, δ): 3.45-3.72 (5H, m), 4.61 (2H, d, J=5 Hz), 4.92(1H, t, J=5 Hz), 6.93 (1H, d, J=8 Hz), 7.42-7.57 (3H, m), 7.82 (1H, s),7.85-7.98 (3H, m), 8.13 (1H, dd, J=8, 2 Hz), 8.67 (1H, d, J=2 Hz), 9.33(1H, d, J=8 Hz), 9.46 (1H, m)

[1009] Mass m/z: 394.2 (M⁺−1).

[1010] Preparation 100

[1011] 2-Fluoro-N-12-(2-methoxyphenyl)ethyl]-5-nitrobenzamide (1.03 g)was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00g) and (2-methoxyphenyl)ethylamine(613 mg) in a manner similar toPreparation 55.

[1012] NMR (DMSO-d₆, δ): 2.81 (2H, t, J=7.5 Hz), 3.44 (2H, q, J=7.5 Hz),3.77 (3H, s), 6.86 (1H, t, J=8 Hz), 6.95 (1H, d, J=8 Hz), 7.11-7.24 (2H,m), 7.57 (1H, t, J=8 Hz), 8.27-8.41 (2H, m), 8.65 (1H, br).

EXAMPLE 100

[1013] 2-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide (198 mg) wasobtained as yellow powders from2-fluoro-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide (200 mg) and2-amino-1,3-propanediol (85.9 mg) in a manner similar to Example 1(1).

[1014] NMR (DMSO-d₆, δ): 2.83 (2H, t, J=7.5 Hz), 3.42 (2H, q, J=7.5 Hz),3.48-3.68 (5H, m), 3.79 (3H, s), 4.92 (2H, t, J=5 Hz), 6.84-6.95 (2H,m), 6.97 (1H, d, J=8 Hz), 7.12-7.27 (2H, in), 8.10 (1H, dd, J=8, 2 Hz),8.47 (1H, d, J=2 Hz), 8.83 (1H, m), 9.17 (1H, d, J=8 Hz)

[1015] Mass m/z: 388.3 (M⁺−1).

[1016] Preparation 101

[1017] N-(4-Ethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (2.51 g)was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid(1.50 g) and 4-ethoxy-3-methoxybenzylamine(1.51 g) in a manner similarto Preparation 55.

[1018] NMR (DMSO-d₆, δ); 1.31 (3H, t, J=7 Hz), 3.75 (3H, s), 3.98 (2H,q, J=7 Hz), 4.42 (2H, d, J=7 Hz), 6.82-6.97 (3H, m), 7.62 (1H, m),8.39-8.44 (2H, m), 9.11 (1H, br).

EXAMPLE 101(1)

[1019]2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitrobenzamide(314 mg) was obtained as yellow powders fromN-(4-ethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (300 mg) andtrans-1,4-cyclohexanediamine (295 mg) in a manner similar to Example 1(1).

[1020] NMR (DMSO-d₆, δ); 1.15-1.35 (4H, br), 1.30 (3H, t, J=7 Hz),1.73-1.85 (2H, br), 1.94-2.05 (2H, br), 2.56-2.70 (1H, br), 3.40-3.50(1H, br), 3.74 (3H, s), 3.97 (2H, q, J=7 Hz), 4.36 (2H, d, J=7 Hz),6.80-6.96 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.02(1H, d, J=8 Hz), 9.31 (1H, br)

[1021] Mass m/z: 441 (M⁺).

EXAMPLE 101(2)

[1022]N-(4-Ethoxy-3-methoxybenzyl)-2-(trans-4-formamidocyclohexylamino)-5-nitrobenzamide(115 mg) was obtained as yellow powders from2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitrobenzamide(150 mg) in a manner similar to Example 73(2).

[1023] NMR (DMSO-d₆, δ); 1.31 (3H, t, J=7 Hz), 1.25-1.45 (4H, br),1.75-1.90 (2H, br), 1.94-2.10 (2H, br), 3.48-3.55 (1H, br), 3.52-3.62(1H, br), 3.75 (3H, s), 3.97 (2H, q, J=7 Hz), 4.36 (2H, d, J=7 Hz),6.80-6.96 (4H, m), 7.95 (1H, s), 8.03 (1H, br), 8.10 (1H, dd, J=4, 8Hz), 8.60 (1H, d, J=4 Hz), 9.03 (1H, d, J=8 Hz), 9.32 (1H, br)

[1024] Mass m/z: 469 (M⁺).

[1025] Preparation 102 (1)

[1026] A solution of sodium sulphite (10.6 g) in water (20 mL) waswarmed to 80° C. and slowly added with stirring to a solution of5-chlorosulfonyl-2-fluorobenzoic acid (10 g) in acetone (10 mL),saturated aqueous sodium carbonate being added simultaneously forkeeping the liquid in alkaline. The mixture was stirred at 60° C. forone and a half hours, and concentrated in vacuo. The residue wassuspended in a mixture of ethanol (20 mL) and water (20 mL), theniodomethane (2.61 mL) was added to the mixture. The reaction mixture wasstirred for 2 hours at 60° C. and for an hour at 100° C. After coolingto ambient temperature, ethanol was removed in vacuo. The resultantaqueous solution was acidified with concentrated hydrochloric acid. Theaqueous solution was extracted with chloroform (3 times), and thecombined organic layer was dried over magnesium sulfate. Afterevaporation of the solvent, the residual oil was crystallized fromethanol to give 2-fluoro-5-methanesulfonylbenzoic acid (563.6 mg) as acolorless solid.

[1027] mp 194-195° C.

[1028] NMR (DMSO-d₆, δ); 3.29 (3H, s), 7.63 (1H, dd, J=10.5, 8.5 Hz),8.19 (1H, ddd, J=8.5, 7.0, 2.5 Hz), 8.37 (1H, dd, J=7.0, 2.5 Hz).

[1029] Mass m/z: 217 (M⁺−1)

[1030] Preparation 102(2)

[1031] N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5-methanesulfonylbenzamide(313.9 mg) was obtained as an off-white solid substance from2-fluoro-5-methanesulfonylbenzoic acid (250 mg) and4-chloro-3-methoxybenzylamine (203 mg) in a manner similar to

[1032] Preparation 55.

[1033] mp. 121-123° C.

[1034] NMR (DMSO-d₆, δ); 3.28 (3H, s), 3.85 (3H, s), 4.49 (2H, d, J=6.0Hz), 6.94 (1H, dd, J=8.0, 2.0 Hz), 7.15 (1H, d, J=2.0 Hz), 7.40 (1H, d,J=8.0 Hz), 7.63 (1H, dd, J=10.0, 8.5 Hz), 8.10 (1H, m), 8.16 (1H, dd,J=6.5, 2.5 Hz), 9.17 (1H, brt, J=6.0 Hz)

[1035] Mass m/z: 370 (M⁺−1).

EXAMPLE 102

[1036]N-(4-Chloro-3-methoxybenzyl)-2-(trans4-hydroxycyclohex-ylamino)-5-methanesulfonylbenzamide(57.2 mg) was obtained as an off-white solid substance fromN-(4-chloro-3-methoxybenzyl)-2-fluoro-5-methanesulfonylbenzamide (80 mg)and trans-4-aminocyclohexanol (49.6 mg) in a manner similar to Example1(1).

[1037] mp. 234-235.5° C.

[1038] NMR (DMSO-d₆, δ); 1.15-1.41 (4H, m), 1.76-1.86 (2H, m), 1.90-2.02(2H, m), 3.10 (3H, s), 3.38-3.53 (2H, m), 3.84 (3H, s), 4.43 (2H, d, J=6Hz), 4.60 (1H, d, J=4 Hz), 6.89 (1H, dd, J=9, 2 Hz), 6.91 (1H, d, J=9Hz), 7.12 (1H, d, J=2 Hz), 7.38 (1H, d, J=8.5 Hz), 7.70 (1H, dd, J=8.5,2.5 Hz), 8.11 (1H, d, J=2.5 Hz), 8.49 (1H, d, J=8 Hz), 9.20 (1H, t, J=6Hz)

[1039] Mass m/z: 465 (M⁺−1).

[1040] Preparation 103

[1041] 2-Fluoro-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide (1.34 g)was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid(1.16 g) and 3-fluoro-4-methoxybenzylamine hydrochloride (1.00 g) in amanner similar to Preparation 55. m.p. 112° C.

[1042] NMR (DMSO-d₆, δ): 3.82 (3H, s), 4.42 (1H, d, J=6 Hz), 7.06-7.23(3H, m), 7.62 (1H, dd, J=9, 9 Hz), 8.37-8.47 (2H, m), 9.15 (1H, t, J=6Hz)

[1043] Mass m/z: 321 (M⁺).

EXAMPLE 103

[1044]N-(3-Fluoro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide(230 mg) was obtained as yellow powders from2-fluoro-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide (263 mg) and2-amino-1,3-propanediol (112 mg) in a manner similar to Example 1 (1).m.p. 130-132° C.

[1045] NMR (DMSO-d₆, δ): 3.45-3.70 (5H, m), 3.81 (3H, s), 4.36 (1H, d,J=6 Hz), 4.91 (2H, t, J=5 Hz), 6.92 (1H, d, J=10 Hz), 7.06-7.21 (3H, m),8.12 (1H, dd, J=10, 2 Hz), 8.59 (1H, d, J=3 Hz), 9.23-9.35 (2H, m)

[1046] Mass m/z: 392 (M⁺).

[1047] Preparation 104

[1048] N-(3-Chloro-4-fluorobenzyl)-2-fluoro-5-nitrobenzamide (976 mg)was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid(1000 mg) and 3-chloro-4-fluorobenzylamine (948 mg) in a manner similarto Preparation 55.

[1049] NMR (DMSO-d₆, δ): 4.49 (2H, d, J=6 Hz), 7.32-7.46 (2H, m), 5.57(1H, d, J=8 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.53 (2H, m), 9.21 (1H,t, J=6 Hz)

[1050] Mass m/z: 325 (M⁺).

EXAMPLE 104

[1051]N-(3-Chloro-4-fluorobenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide(211 mg) was obtained as yellow powders from2-fluoro-N-(3-chloro-4-fluorobenzyl)-5-nitrobenzamide (207 mg) and2-amino-1,3-propanediol (115 mg) in a manner similar to Example 1(1).

[1052] m.p. 235-238° C.

[1053] NMR (DMSO-d₆, δ): 3.28-3.70 (5H, m), 4.42 (2H, d, J=6 Hz), 4.93(2H, t, J=5 Hz), 6.93 (1H, d, J=10 Hz), 7.30-7.44 (3H, m), 7.54 (1H, dd,J=6, 2 Hz), 8.13 (1H, dd, J=10, 3 Hz), 8.62 (1H, d, J=3 Hz), 9.28 (1H,d, J=8 Hz), 9.37 (1H, t, J=5 Hz)

[1054] Mass m/z: 396 (M⁺).

[1055] Preparation 105

[1056] N-(3-Chloro-4-methylbenzyl)-2-fluoro-5-nitrobenzamide (2.25 g)was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid(1.65 g) and 3-chloro-4-methylbenzylamine (1.46 g) in a manner similarto Preparation 55.

[1057] NMR (DMSO-d₆, δ): 2.31 (3H, s), 4.46 (2H, d, J=6 Hz), 7.23 (1H,dd, J=8, 1 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, d, J=1 Hz), 7.64 (1H,dd, J=9, 9 Hz), 8.37-8.50 (2H, m), 9.19 (1H, t, J=6 Hz)

[1058] Mass m/z: 321 (M⁺).

EXAMPLE 105

[1059](S)-N-(3-Chloro-4-methylbenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide(131 mg) was obtained as yellow powders fromN-(3-chloro-4-methylbenzyl)-2-fluoro-5-nitrobenzamide (184 mg) and(S)-2-amino-1-propanol (64 mg) in a manner similar to Example 1 (1).

[1060] m.p. 178-179° C.

[1061] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=6 Hz), 2.30 (3H, s), 3.45 (2H,m), 3.76 (1H, m), 4.40 (2H, d, J=5 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H,d, J=9 Hz), 7.21 (1H, dd, J=8, 1 Hz), 7.32 (1H, d, J=8 Hz), 8.12 (1H,dd, J=9, 3 Hz), 8.61 (1H, d, J=3 Hz), 9.16 (1H, d, J=8 Hz), 9.36 (1H, t,J=5 Hz)

[1062] Mass m/z: 376 (M⁺).

[1063] Preparation 106

[1064] 2-Fluoro-N-(3-methoxy-4-methylbenzyl)-5-nitrobenzamide (3.31 g)was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (2.60g) and 3-methoxy-4-methylbenzylamine (2.30 g) in a manner similar toPreparation 55.

[1065] NMR (DMSO-d₆, δ): 2.12 (3H, s), 3.78 (3H, s), 4.46 (2H, d, J=6Hz), 6.83 (1H, d, J=7.5 Hz), 6.94 (1H, s), 7.10 (1H, d, J=7.5 Hz), 7.63(1H, dd, J=10, 9 Hz), 8.37-8.47 (2H, m), 9.15 (1H, t, J=6 Hz)

[1066] Mass m/z: 317 (M⁺).

EXAMPLE 106

[1067] 2-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-N-(3-methoxy-4-methylbenzyl)-5-nitrobenzamide (173 mg) wasobtained as yellow powders from2-fluoro-N-(3-methoxy-4-methylbenzyl)-5-nitrobenzamide (171 mg)2-amino-1,3-propanediol (98 mg) in a manner similar to Example 1(1).

[1068] m.p. 160-162° C.

[1069] NMR (DMSO-d₆, δ): 2.11 (3H, s), 3.46-3.60 (4H, m), 3.63 (1H, m),3.77 (3H, s), 4.40 (2H, d, J=6 Hz), 4.92 (2H, t, J=5 Hz), 6.80 (1H, brd, J=8 Hz), 6.92 (1H, s), 6.92 (1H, d, J=10 Hz), 7.08 (1H, d, J=8 Hz),8.12 (1H, dd, J=10, 3 Hz), 8.59 (1H, d, J=3 Hz), 9.21 (1H, d, J=8 Hz),9.30 (1H, t, J=6 Hz)

[1070] Mass m/z: 388 (M⁺).

[1071] Preparation 107

[1072] N-(3,5-Dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (3.08 g) wasobtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (2.12g) and 3,5-dimethoxybenzylamine (2.01 g) in a manner similar toPreparation 55.

[1073] NMR (DMSO-d₆, δ): 3.73 (6H, s), 4.44 (2H, d, J=6 Hz), 6.40 (1H,dd, J=2, 2 Hz), 6.52 (2H, d, J=2 Hz), 7.64 (1H, dd, J=9, 9 Hz),8.37-8.48 (2H, m), 9.16 (1H, t, J=6 Hz)

[1074] Mass m/z: 333 (M⁺).

EXAMPLE 107

[1075](S)-N-(3,5-Dimethoxybenzyl)-2-(2-hydroxy-1-methylethyl)amino-5-nitrobenzamide(178 mg) was obtained as yellow powders fromN-(3,5-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (169 mg) and(S)-2-amino-1-propanol (57 mg) in a manner similar to Example 1(1).

[1076] m.p. 98-101° C.

[1077] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=7 Hz), 3.46 (2H, m), 3.73 (6H,s), 3.75 (1H, m), 4.37 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.39 (1H,dd, J=2, 2 Hz), 6.49 (2H, d, J=2 Hz), 6.90 (1H, d, J=10 Hz), 8.12 (1H,dd, J=10, 2 Hz), 8.61 (1H, d, J=2 Hz), 9.11 (1H, d, J=8 Hz), 9.32 (1H,t, J=6 Hz)

[1078] Mass m/z: 388(M⁺).

[1079] Preparation 108

[1080] 2-Fluoro-5-nitro-N-(4-phenoxybenzyl)benzamide (1.22 g) wasobtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g)and 4-phenoxybenzylamine (1.13 g) in a manner similar to Preparation 55.

[1081] NMR (DMSO-d₆, δ): 4.49 (2H, d, J=6 Hz), 6.95-7.05 (4H, m), 7.13(1H, dd, J=7.5, 7.5 Hz), 7.32-7.45 (4H, m), 7.63 (1H, dd, J=9, 9 Hz),8.37-8.50 (2H, m), 9.18 (1H, t, J=6 Hz)

[1082] Mass m/z: 365 (M⁺).

EXAMPLE 108

[1083] (R)-2-(2-Hydroxy-1-methylethyl)amino-5-nitro-N-(4-phenoxybenzyl)benzamide (197 mg) was obtained asyellow powders from 2-fluoro-5-nitro-N-(4-phenoxybenzyl)benzamide (207mg) and (R)-2-amino-1-propanol (85 mg) in a manner similar to Example1(1).

[1084] m.p. 127-129° C.

[1085] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=7 Hz), 3.46 (2H, m), 3.76 (1H,m), 4.43 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H, d, J=7 Hz),6.99 (4H, d, J=9 Hz), 7.13 (1H, t, J=8 Hz), 7.30-7.45 (4H, m), 8.12 (1H,dd, J=10, 3 Hz), 8.62 (1H, d, J=3 Hz), 9.20 (1H, d, J=8 Hz), 9.37 (1H,t, J=6 Hz)

[1086] Mass m/z: 420 (M⁺).

[1087] Preparation 109

[1088] 2-Fluoro-5-nitro-N-(4-phenylbenzyl)benzamide (1.44 g) wasobtained from 2-fluoro-5-nitrobenzoic acid (827 mg) and4-phenylbenzylamine (860 mg) in a manner similar to Preparation 55.

[1089] NMR (DMSO-d₆, δ): 4.55 (2H, d, J=6 Hz), 7.36 (1H, dd, J=7.5, 7.5Hz), 7.40-7.51 (4H, m), 7.57-7.72 (5H, m), 8.37-8.52 (2H, m), 9.23 (1H,t, J=6 Hz)

[1090] Mass m/z: 349 (M⁺).

EXAMPLE 109

[1091] (R)-2-(2-Hydroxy-1-methylethyl)amino-5-nitro-N-(4-phenybenzyl)benzamide (167 mg) was obtained as yellowpowders from 2-fluoro-5-nitro-N-(4-phenybenzyl)benzamide (178 mg) and(R)-2-amino-1-propanol (76 mg) in a manner similar to Example 1(1).

[1092] m.p. 168.5-170.5° C.

[1093] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=6 Hz), 3.46 (2H, m), 3.77 (1H,m), 4.49 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H, d, J=10 Hz),7.30-7.52 (5H, m), 7.60-7.71 (4H, m), 8.13 (1H, dd, J=10, 2 Hz), 8.65(1H, d, J=2 Hz), 9.21 (1H, d, J=8 Hz), 9.42 (2H, t, J=6 Hz)

[1094] Mass m/z: 404 (M⁺).

EXAMPLE 110(1)

[1095] 2-(Cyclopentylamino)-N-(4-ethoxycarbonylbenzyl)-5-nitrobenzamide(760 mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (500 mg) and4-ethoxycarbonylbenzylamine (430 mg) in a manner similar to Example 30.

[1096] NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.59-1.85 (6H, m),2.00-2.15 (2H, m), 3.91 (1H, m), 4.37 (2H, q, J=7 Hz), 4.66 (2H, d, J=7Hz), 6.64 (1H, br), 6.69 (1H, d, J=8 Hz), 7.40 (2H, d, J=8 Hz), 8.03(2H, d, J=8 Hz), 8.16 (1H, dd, J=4, 8 Hz), 8.37 (1H, d, J=4 Hz), 8.84(1H, br)

[1097] Mass m/z: 410 (M⁺).

EXAMPLE 110(2)

[1098] A mixture of2-(cyclopentylamino)-N-(4-ethoxycarbonylbenzyl)-5-nitrobenzamide (645mg), ethanol (30 mL) and 1N-sodium hydroxide solution (5 mL) was heatedfor 2 hours under reflux. The mixture was acidified with 1N-hydrochloric acid to pH 4 and the organic solvent was removed byevaporation. The resulting precipitates were collected by filtration andwashed with water and diethyl ether to giveN-(4-carboxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as yellowpowders (541 mg).

[1099] NMR (DMSO-d₆, δ): 1.38-1.50 (2H, m), 1.56-1.70 (4H, m), 2.04 (2H,m), 3.97 (1H, m), 4.52 (2H, d, J=7 Hz), 6.87 (1H, d, J=8 Hz), 7.42 (2H,d, J=8 Hz), 7.90 (2H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.66 (1H, d,J=4 Hz), 9.16 (1H, d, J=8 Hz), 9.46 (1H, br)

[1100] Mass m/z: 382 (M⁺).

EXAMPLE 110(3)

[1101] A mixture ofN-(4-carboxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (120 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90.0 mg)and 1-hydroxybenzotriazole (63.4 mg) in anhydrous dimethylformamide (2mL) was stirred for an hour at ambient temperature. After addition of28% ammonia solution (10 drops), the mixture was stirred for 15 hours atambient temperature and poured into water. The resulting precipitateswere collected by filtration, washed with water and purified by a silicagel column chromatography eluting with 10% methanol in chloroform. Theobtained product was triturated with diisopropyl ether to giveN-(4-carbamoylbenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (107 mg) asyellow powders.

[1102] NMR (DMSO-d₆, δ): 1.39-1.52 (2H, m), 1.56-1.73 (4H, m), 1.98-2.10(2H, m), 3.98 (1H, m), 4.48 (2H, d, J=7 Hz), 6.87 (1H, d, J=8 Hz), 7.31(1H, br), 7.38 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 7.91 (1H, br),8.13 (1H, dd, J=4, 8 Hz), 8.67 (1H, d, J=4 Hz), 9.15 (1H, d, J=8 Hz),9.44 (1H, br)

[1103] Mass m/z: 383 (M⁺).

EXAMPLE 111(1)

[1104] N-(4-Aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (270 mg)was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoicacid (300 mg) and 4-aminobenzylamine (176 mg) in a manner similar toExample 30.

[1105] NMR (DMSO-d₆, δ): 1.40-1.51 (2H, m), 1.55-1.75 (4H, m), 1.98-2.10(2H, m), 3.97 (1H, m), 4.24 (2H, d, J=7 Hz), 4.97 (2H, br), 6.52 (2H, d,J=8 Hz), 6.86 (1H, d, J=8 Hz), 6.97 (2H, d, J=8 Hz), 8.12 (1H, dd, J=4,8 Hz), 8.57 (1H, d, J=4 Hz), 9.10-9.25 (2H, m)

[1106] Mass m/z: 355 (M⁺).

EXAMPLE 111(2)

[1107] To a mixture ofN-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (126 mg) andtriethylamine (0.119 mL) in anhydrous dichloromethane (20 mL) was addedacetyl chloride (33.5 mg). After stirring for 2 hours at ambienttemperature, the mixture was washed with an aqueous saturated sodiumbicarbonate solution, water and brine. The resultant was dried overmagnesium sulfate and evaporated in vacuo. The residue was purified by asilica gel column chromatography eluting with 10% methanol inchloroform. The obtained product was triturated with diisopropyl etherto give N-(4-acetamidobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide asyellow powders (135 mg).

[1108] NMR (DMSO-d₆, δ): 1.38-1.54 (2H, m), 1.60-1.75 (4H, m), 1.98-2.10(5H, br), 3.96 (1H, m), 4.38 (2H, d, J=7 Hz), 6.86 (1H, d, J=8 Hz), 7.25(2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.62 (1H,s), 9.17 (1H, d, J=8 Hz), 9.35 (1H, br), 9.92 (1H, s)

[1109] Mass m/z: 395 (M⁺).

[1110] Preparation 112(1)

[1111] N-[4-[Bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl]phthalimide(2.14 g) was obtained as colorless powders from4-[bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl bromide (2.00 g) andpotassium phthalimide (969 mg) in a manner similar to Preparation 91(3).

[1112] NMR (CDCl₃, δ): 1.42 (18H, s), 4.99 (2H, s), 7.00 (1H, dd, J=4, 8Hz), 7.22 (2H, m), 7.75 (2H, m), 7.87 (2H, m). Preparation 112(2)4-(tert-Butoxycarbonylamino)-2-chlorobenzylamine (950 mg) was obtainedas colorless oil fromN-[4-[bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl]phthalimide (2.00 g)in a manner similar to Preparation 91(4).

[1113] NMR (CDCl₃, δ): 1.50 (9H, s), 3.87 (2H, s), 7.14 (1H, m), 7.25(2H, m)

[1114] Mass m/z: 257 (M⁺).

EXAMPLE 112(1)

[1115] N-[4-(tert-Butoxycarbonyl)amino-2-chlorobenzyl]-2-(cyclopentylamino)-5-nitrobenzamide (206 mg) wasobtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoic acid(200 mg) and 4-(tert-butoxycarbonylamino)-2-chlorobenzylamine (246 mg)in a manner similar to Example 51.

[1116] NMR (CDCl₃, δ): 1.50 (9H, s), 1.59-1.85 (6H, m), 2.06 (2H, m),3.90 (1H, m), 4.61 (2H, d, J=7 Hz), 6.48 (1H, br), 6.54 (1H, br), 6.67(1H, d, J=8 Hz), 7.14 (1H, dd, J=4, 8 Hz), 7.32 (1H, d, J=8 Hz), 7.61(1H, d, J=4 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.28 (1H, d, J=4 Hz), 8.77(1H, br)

[1117] Mass m/z: 487 (M⁺).

EXAMPLE 112(2)

[1118] To a solution ofN-[4-(tert-butoxycarbonyl)amino-2-chlorobenzyl]-2-(cyclopentylamino)-5-nitrobenzamide(141 mg) in anhydrous ethyl acetate (2 mL) was added 4N-hydrochloricacid ethyl acetate solution (4 mL). After stirring for 2 hours atambient temperature, the mixture was partitioned between 1N-sodiumhydroxide solution and chloroform. The separated organic layer waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was triturated with diisopropyl ether to giveN-(4-amino-2-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide asyellow powders (102 mg).

[1119] NMR (DMSO-d₆, δ): 1.39-1.52 (2H, m), 1.55-1.74 (4H, m), 1.96-2.10(2H, m), 3.97 (1H, m), 4.33 (2H, d, J=7 Hz), 5.32 (2H, s), 6.49 (1H, dd,J=4, 8 Hz), 6.62 (1H, d, J=4 Hz), 6.85 (1H, d, J=8 Hz), 7.03 (1H, d, J=8Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 9.07 (1H, d, J=8Hz), 9.14 (1H, br)

[1120] Mass m/z: 389 (M⁺).

[1121] Preparation 113(1)

[1122] N-(2-Chloro-4-methoxybenzyl)phthalimide (2.40 g) was obtained ascolorless powders from 2-chloro-4-methoxybenzyl bromide (2.00 g) andpotassium phthalimide (1.86 g) in a manner similar to Preparation 91(3).

[1123] NMR (CDCl₃, δ): 3.77 (3H, s), 4.93 (2H, s), 6.74 (1H, dd, J=4, 8Hz), 6.92 (1H, d, J=4 Hz), 7.22 (1H, d, J=8 Hz), 7.73 (2H, m), 7.86 (2H,m).

[1124] Preparation 113(2)

[1125] 2-Chloro-4-methoxybenzylamine (630 mg) was obtained as paleyellow oil from N-(2-Chloro-4-methoxybenzyl)phthalimide (1.00 g) in amanner similar to Preparation 91(4).

[1126] NMR (CDCl₃, δ): 3.79 (3H, s), 3.86 (2H, s), 6.78 (1H, dd, J=4, 8Hz), 6.92 (1H, d, J=4 Hz), 7.27 (1H, m)

[1127] Mass m/z: 154 (M⁺).

EXAMPLE 113

[1128]N-(2-Chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (146mg) was obtained as yellow powders from2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and2-chloro-4-methoxybenzylamine (82.3 mg) in a manner similar toPreparation 1.

[1129] NMR (CDCl₃, δ): 1.59-1.85 (6H, m), 2.00-2.13 (2H, m), 3.80 (3H,s), 3.90 (1H, m), 4.62 (2H, d, J=7 Hz), 6.52 (1H, br), 6.67 (1H, d, J=8Hz), 6.80 (1H, dd, J=4, 8 Hz), 6.97 (1H, d, J=4 Hz), 7.34 (1H, d, J=8Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 8.78 (1H, br)

[1130] Mass m/z: 404 (M⁺).

[1131] Preparation 114

[1132] A solution of 3-chloro-4-methoxybenzylamine (234 mg) inN,N-dimethylformamide (5 mL) was added dropwise to a solution of5-bromoisatoic anhydride (300 mg) in N,N-dimethylformamide (3 mL). Thereaction mixture was stirred for an hour at ambient temperature. Themixture was poured into a mixture of water and ethyl acetate. Theprecipitates were collected by filtration and washed with 2-propanol togive 2-amino-5-bromo-N-(3-chloro-4-methoxybenzyl)benzamide (245 mg) aswhite powders.

[1133] NMR (DMSO-d₆, δ): 3.83 (3H, s), 4.32 (2H, d, J=6 Hz), 6.61 (2H,s), 6.68 (1H, d, J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.25 (1H, dd, J=2, 9Hz), 7.27 (1H, dd, J=2, 9 Hz), 7.35 (1H, d, J=2 Hz), 7.69 (1H, d, J=2Hz), 8.88 (1H, t, J=6 Hz).

EXAMPLE 114

[1134] A solution of 97% sulfuric acid (79 mg) in tetrahydrofuran (0.5mL) was added to a mixture of2-amino-5-bromo-N-(3-chloro-4-methoxybenzyl)benzamide (199 mg),cyclopentanone (68 mg) and sodium borohydride (31 mg) in tetrahydrofuran(3 mL). The mixture was stirred for an hour at ambient temperature. Thencyclopentanone (68 mg), sodium borohydride (31 mg) and a solution of 97%sulfuric acid (80 mg) in tetrahydrofuran (0.5 mL) were added to thereaction mixture. After stirring for additional 2 hours at ambienttemperature, the reaction mixture was diluted with water. The resultantwas made alkaline with an aqueous saturated sodium bicarbonate solutionand extracted with ethyl acetate. The extract was washed with brine,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by a preparative silica gel thin layer chromatography developedby 25% ethyl acetate in hexane. The obtained substance was dissolved indiethyl ether, and 4 N-hydrogen chloride solution in ethyl acetate (0.3mL) was added thereto. The mixture was concentrated in vacuo and theresidue was triturated with diethyl ether to give5-bromo-N-(3-chloro-4-methoxybenzyl)-2-(cyclopentylamino)benzamidehydrochloride (198 mg) as white powders.

[1135] NMR (DMSO-d₆, δ): 1.38 (2H, m), 1.50-1.70 (4H, m), 1.95 (2H, m),3.77 (1H, m), 3.83 (3H, s), 4.32 (1H, d, J=6 Hz), 6.87 (1H, d, J=9 Hz),7.11 (1H, d, J=9 Hz), 7.25 (1H, dd, J=2, 19 Hz), 7.35 (1H, d, J=2 Hz),7.40 (1H, dd, J=2, 9 Hz), 7.77 (1H, d, J=2 Hz), 8.99 (1H, t, J=6 Hz)

[1136] Mass: (ESI+) 437,439 (M+H), (ESI−) 435,437 (M−H).

[1137] Preparation 115

[1138] 2-Amino-5-chloro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (321 mg)was obtained as white powders from 5-chloroisatoic anhydride (300 mg)and (1,3-benzodioxol-5-ylmethyl)amine (275 mg) in a manner similar toPreparation 114.

[1139] NMR (DMSO-d₆, δ): 4.30 (2H, d, J=6 Hz), 5.98 (2H, s), 6.58 (2H,s), 6.72 (1H, d, J=9 Hz), 6.78 (1H, dd, J=1, 8 Hz), 6.86 (1H, d, J=8Hz), 6.87 (1H, d, J=1 Hz), 7.17 (1H, dd, J=2, 9 Hz), 7.58 (1H, d, J=2Hz), 8.84 (1H, t, J=6 Hz)

[1140] Mass: (ESI+) 305, 307 (M+H), (ESI−) 303, 305 (M−H).

EXAMPLE 115

[1141]5-Chloro-2-(cyclopentylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamidehydrochloride (140 mg) was obtained as white crystals from2-amino-5-chloro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (135 mg) andcyclopentanone (110 mg) in a manner similar to Example 114.

[1142] NMR (DMSO-d₆, δ): 1.32-1.45 (2H, m), 1.50-1.73 (4H, m), 1.90-2.03(2H, m), 4.30 (2H, d, J=6 Hz), 5.98 (2H, s), 6.73 (1H, d, J=9 Hz), 6.77(1H, d, J=8 Hz), 6.86 (1H, d, J=8 Hz), 6.88 (1H, s), 7.29 (1H, brd, J=9Hz), 7.67 (1H, br), 8.95 (1H, t, J=6 Hz)

[1143] Mass: (ESI+) 373, 375 (M+H), (ESI−) 371, 373 (M−H).

[1144] Preparation 116

[1145] To a suspension of 5-nitroisatoic anhydride (300 mg) indimethylformamide (4 mL) was added 2-chlorobenzylamine (245 mg), and themixture was stirred for 15 hours at ambient temperature. The mixture waspartitioned between ethyl acetate and water. The separated organic layerwas washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with diisopropyl etherto give 2-amino-N-(2-chlorobenzyl)-5-nitrobenzamide as yellow powders(397 mg).

[1146] NMR (DMSO-d₆, δ): 4.50 (2H, d, J=7 Hz), 6.82 (1H, d, J=8 Hz),7.27-7.41 (3H, m), 7.47 (1H, d, J=8 Hz), 7.80 (2H, br), 8.05 (1H, dd,J=4, 8 Hz), 8.65 (1H, d, J=4 Hz), 9.28 (1H, br)

[1147] Mass m/z: 304 (M⁺).

EXAMPLE 116

[1148] N-(2-Chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide (152 mg)was obtained as yellow powders from2-amino-N-(2-chlorobenzyl)-5-nitrobenzamide (150 mg) and cyclopentanone(61.9 mg) in a manner similar to Preparation 30(1).

[1149] NMR (CDCl₃, δ): 1.58-1.84 (6H, m), 2.00-2.15 (2H, m), 3.88 (1H,m), 4.68 (2H, d, J=7 Hz), 6.60 (1H, br), 6.68 (1H, d, J=8 Hz), 7.27 (2H,m), 7.42 (2H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.78(1H, br).

[1150] Mass m/z: 372 (M⁺).

[1151] Preparation 117

[1152] 2-Amino-N-(3-chlorobenzyl)-5-nitrobenzamide (400 mg) was obtainedas yellow powders from 5-nitroisatoic anhydride (300 mg) and3-chlorobenzylamine (245 mg) in a manner similar to Preparation 114.

[1153] NMR (DMSO-d₆, δ): 4.42 (2H, d, J=7 Hz), 6.80 (1H, d, J=8 Hz),7.28-7.40 (4H, m), 7.82 (2H, br), 8.03 (1H, dd, J=4, 8 Hz), 8.59 (1H, d,J=4 Hz), 9.28 (1H, br)

[1154] Mass m/z: 304 (M⁺).

EXAMPLE 117

[1155] N-(3-Chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (136 mg)was obtained as yellow powders from2-amino-N-(3-chlorobenzyl)-5-nitrobenzamide (150 mg) and cyclopentanone(61.9 mg) in a manner similar to Preparation 30(1).

[1156] NMR (CDCl₃, δ): 1.58-1.84 (6H, m), 2.00-2.15 (2H, m), 3.88 (1H,m), 4.58 (2H, d, J=7 Hz), 6.60 (1H, br), 6.68 (1H, d, J=8 Hz), 7.20-7.35(4H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.85 (1H, br)

[1157] Mass m/z: 372 (M⁺).

[1158] Preparation 118

[1159] 2-Amino-N-(4-chlorobenzyl)-5-nitrobenzamide (407 mg) was obtainedas yellow powders from 5-nitroisatoic anhydride (300 mg) and4-chlorobenzylamine (245 mg) in a manner similar to Preparation 114.

[1160] NMR (DMSO-d₆, δ): 4.42 (2H, d, J=7 Hz), 6.80 (1H, d, J=8 Hz),7.32-7.44 (4H, m), 7.82 (2H, br), 8.03 (1H, dd, J=4, 8 Hz), 8.58 (1H, d,J=4 Hz), 9.30 (1H, br)

[1161] Mass m/z: 304 (M⁺).

EXAMPLE 118

[1162] N-(4-Chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (97.7mg) was obtained as yellow powders from2-amino-N-(4-chlorobenzyl)-5-nitrobenzamide (150 mg) and cyclopentanone(61.9 mg) in a manner similar to Preparation 30(1).

[1163] NMR (CDCl₃, δ): 1.58-1.84 (6H, m), 2.00-2.15 (2H, m), 3.88 (1H,m), 4.57 (2H, d, J=7 Hz), 6.54 (1H, br), 6.68 (1H, d, J=8 Hz), 7.27-7.36(4H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.78 (1H, br)

[1164] Mass m/z: 372 (M⁺).

[1165] Preparation 119

[1166] 2-Amino-N-hexyl-5-nitrobenzamide (1.09 g) was obtained as yellowpowders from 5-nitroisatoic anhydride (1.00 g) and hexylamine (583 mg)in a manner similar to Preparation 114.

[1167] NMR (DMSO-d₆, δ): 0.85 (3H, br), 1.30 (6H, br), 1.52 (2H, br),3.20 (2H, m), 6.78 (1H, d, J=8 Hz), 7.75 (2H, br), 8.02 (1H, dd, J=4, 8Hz), 8.48 (1H, d, J=4 Hz), 8.67 (1H, br)

[1168] Mass m/z: 264 (M⁺).

EXAMPLE 119

[1169] 2-(Cyclopentylamino)-N-hexyl-5-nitrobenzamide (98.0 mg) wasobtained as yellow powders from 2-amino-N-hexyl-5-nitrobenzamide (100mg) and cyclopentanone (47.6 mg) in a manner similar to Preparation30(1).

[1170] NMR (CDCl₃, δ): 0.90 (3H, br), 1.28-1.48 (6H, br), 1.58-1.83 (8H,br), 2.07 (2H, br), 3.38 (2H, m), 3.89 (1H, br), 6.20 (1H, br), 6.63(1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 8.82(1H, br)

[1171] Mass m/z: 332 (M⁺).

EXAMPLE 120

[1172] N-Hexyl-5-nitro-2-[(2-thienylmethyl)amino]benzamide (124 mg) wasobtained as yellow powders from 2-amino-N-hexyl-5-nitrobenzamide (200mg) and 2-thiophenecarboxaldehyde (93.0 mg) in a manner similar toPreparation 30(1).

[1173] NMR (CDCl₃, δ): 0.90 (3H, br), 1.28-1.48 (6H, br), 1.60-1.70 (2H,br), 3.41 (2H, m), 4.66 (2H, d, J=7 Hz), 6.28 (1H, br), 6.72 (1H, d, J=8Hz), 6.98 (1H, m), 7.03 (1H, m), 7.24 (1H, m), 8.15 (1H, dd, J=4, 8 Hz),8.33 (1H, d, J=4 Hz), 9.17 (1H, br)

[1174] Mass m/z: 360(M⁺).

EXAMPLE 121

[1175] 2-(Cycloheptylamino)-N-hexyl-5-nitrobenzamide (225 mg) wasobtained as yellow powders from 2-amino-N-he,xyl-5-nitrobenzamide (200mg) and cycloheptanone (211 mg) in a manner similar to Preparation30(1).

[1176] NMR (CDCl₃, δ): 0.89 (3H, br), 1.28-1.45 (6H, br), 1.48-1.78(12H, br), 1.93-2.06 (2H, br), 3.40 (2H, m), 3.60 (1H, m), 6.20 (1H,br), 6.57 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.30 (1H, d, J=4Hz), 8.88 (1H, br)

[1177] Mass m/z: 360 (M⁺).

[1178] Preparation 122

[1179] 2-Amino-N-(5-hydroxypentyl)-5-nitrobenzamide (167 mg) wasobtained as yellow powders from 5-nitroisatoic anhydride (200 mg) and5-amino-1-pentanol (119 mg) in a manner similar to Preparation 114.

[1180] NMR (DMSO-d₆, δ): 1.25-1.60 (6H, m), 3.22 (2H, m), 3.40 (2H, m),4.37 (1H, t, J=7 Hz), 6.78 (1H, d, J=8 Hz), 7.75 (2H, br), 8.02 (1H, dd,J=4, 8 Hz), 8.49 (1H, d, J=4 Hz), 8.68 (1H, br)

[1181] Mass m/z: 266 (M⁺).

EXAMPLE 122

[1182] 2-(Cyclopentylamino)-N-(5-hydroxypentyl)-5-nitrobenzamide (83.5mg) was obtained as yellow powders from2-amino-N-(5-hydroxypentyl)-5-nitrobenzamide (150 mg) and cyclopentanone(142 mg) in a manner similar to Preparation 30(1).

[1183] NMR (CDCl₃, δ): 1.43-1.88 (12H, br), 2.00-2.15 (2H, br), 3.43(2H, m), 3.69 (2H, t, J=7 Hz), 3.83-3.96 (1H, m), 6.55 (1H, br), 6.65(1H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.36 (1H, d, J=4 Hz), 8.86 (1H, br)

[1184] Mass m/z: 334 (M⁺).

[1185] Preparation 123

[1186] 2-Amino-N-(3-ethoxypropyl)-5-nitrobenzamide (332 mg) was obtainedas yellow powders from 5-nitroisatoic anhydride (300 mg) and3-ethoxypropylamine (178 mg) in a manner similar to Preparation 114.

[1187] NMR (DMSO-d₆, δ): 1.10 (3H, t, J-7 Hz), 1.25 (2H, m), 3.29 (2H,m), 3.42 (4H, m), 6.78 (1H, d, J=8 Hz), 7.76 (2H, br), 8.01 (1H, dd,J=4, 8 Hz), 8.48 (1H, d, J=4 Hz), 8.68 (1H, br)

[1188] Mass m/z: 266 (M⁺).

EXAMPLE 123

[1189] 2-(Cyclopentylamino)-N-(3-ethoxypropyl)-5-nitrob enzamide (150mg) was obtained as yellow powders from2-amino-N-(3-ethoxypropyl)-5-nitrobenzamide (150 mg) and cyclopentanone(165 mg) in a manner similar to Preparation 30(1).

[1190] NMR (CDCl₃, δ): 1.28 (3H, t, J=7 Hz), 1.61-1.84 (6H, br), 1.93(2H, m), 2.03-2.12 (2H, m), 3.57 (4H, m), 3.68 (2H, t, J=7 Hz), 3.91(1H, m), 6.67 (1H, d, J=8 Hz), 7.45 (1H, br), 8.15 (1H, dd, J=4, 8 Hz),8.32 (1H, d, J=4 Hz), 9.01 (1H, br)

[1191] Mass m/z: 334 (M⁺).

[1192] Preparation 124

[1193] 2-Amino-N-benzyl-5-nitrobenzamide (1.66 g) was obtained as yellowpowders from 5-nitroisatoic anhydride (1.50 g) and benzylamine (850 mg)in a manner similar to Preparation 114.

[1194] NMR (DMSO-d₆, δ): 4.45 (2H, d, J=7 Hz), 6.80 (1H, d, J=8 Hz),7.26 (1H, m), 7.33 (4H, m), 7.80 (2H, br), 8.01 (1H, dd, J=4, 8 Hz),8.58 (1H, d, J=4 Hz), 9.28 (1H, br)

[1195] Mass m/z: 270 (M⁺).

EXAMPLE 124

[1196] N-Benzyl-2-(cyclobutylamino)-5-nitrobenzamide (210 mg) wasobtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide (200mg) and cyclobutanone (77.5 mg) in a manner similar to preparation30(1).

[1197] NMR (CDCl₃, δ): 1.80-2.10 (4H, m), 2.44-2.55 (2H, m), 4.00 (1H,m), 4.61 (2H, d, J=7 Hz), 6.52 (1H, br), 6.53 (1H, d, J=8 Hz), 7.28-7.42(5H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.31 (1H, d, J=4 Hz), 8.89 (1H, br)

[1198] Mass m/z: 324(M⁺).

EXAMPLE 125

[1199] N-Benzyl-2-cycloheptylamino-5-nitrobenzamide (165 mg) wasobtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide (200mg) and cycloheptanone (372 mg) in a manner similar to Preparation30(1).

[1200] NMR (CDCl₃, δ): 1.44-1.80 (10H, br), 1.95-2.07 (2H, br), 3.63(1H, m), 4.61 (2H, d, J=7 Hz), 6.47 (1H, br), 6.58 (1H, d, J=8 Hz),7.29-7.42 (5H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 8.90(1H, br)

[1201] Mass m/z: 366(M⁺).

EXAMPLE 126

[1202] N-Benzyl-2-(cyclohexylamino)-5-nitrobenzamide (135 mg) wasobtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide (200mg) and cyclohexanone (217 mg) in a manner similar to Preparation 30(1).

[1203] NMR (CDCl₃, δ): 1.27-1.70 (6H, br), 1.80 (2H, br), 2.03 (2H, br),3.46 (1H, br), 4.59 (2H, d, J=7 Hz), 6.46 (1H, br), 6.66 (1H, d, J=8Hz), 7.28-7.40 (5H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz),8.88 (1H, br)

[1204] Mass m/z: 352(M⁺).

[1205] Preparation 127

[1206] 2-Amino-N-(2,4-dichlorobenzyl)-5-nitrobenzamide (437 mg) wasobtained as yellow powders from 5-nitroisatoic anhydride (300 mg) and2,4-dichlorobenzylamine (305 mg) in a manner similar to Preparation 116.

[1207] NMR (DMSO-d₆, δ): 4.48 (2H, d, J=7 Hz), 6.83 (1H, d, J=8 Hz),7.42 (2H, m), 7.63 (1H, s), 7.81 (2H, br), 8.05 (1H, dd, J=4, 8 Hz),8.64 (1H, d, J=4 Hz), 9.29 (1H, br).

EXAMPLE 127

[1208] 2-(Cyclopentylamino)-N-(2,4-dichlorobenzyl)-5-nitrobenzamide (151mg) was obtained as yellow powders from2-amino-N-(2,4-dichlorobenzyl)-5-nitrobenzamide (150 mg) andcyclopentanone (111 mg) in a manner similar to Preparation 30(1).

[1209] NMR (CDCl₃, δ): 1.58-1.88 (6H, m), 2.08 (2H, m), 3.89 (1H, m),4.65 (2H, d, J=7 Hz), 6.67 (1H, d, J=8 Hz), 6.65-6.75 (1H, br), 7.25(1H, m), 7.36 (1H, d, J=8 Hz), 7.43 (1H, d, J=4 Hz), 8.13 (1H, dd, J=4,8 Hz), 8.33 (1H, d, J=4 Hz), 8.75 (1H, br).

[1210] Preparation 128

[1211] 2-Amino-N-(3,4-dichlorobenzyl)-5-nitrobenzamide (444 mg) wasobtained as yellow powders from 5-nitroisatoic anhydride (300 mg) and3,4-dichlorobenzylamine (305 mg) in a manner similar to Preparation 116.

[1212] NMR (DMSO-d₆, δ): 4.43 (2H, d, J=7 Hz), 6.83 (1H, d, J=8 Hz),7.33 (1H, d, J=8 Hz), 7.59 (2H, m), 7.83 (2H, br), 8.04 (1H, dd, J=4, 8Hz), 8.58 (1H, d, J=4 Hz), 9.32 (1H, br).

EXAMPLE 128

[1213] 2-(Cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide(81.8 mg) was obtained as yellow powders from2-amino-N-(3,4-dichlorobenzyl)-5-ntrobenzamide (150 mg) andcyclopentanone (111 mg) in a manner similar to Preparation 30(1).

[1214] NMR (CDCl₃, δ): 1.58-1.86 (6H, m), 2.07 (2H, m), 3.90 (1H, m),4.56 (2H, d, J=7 Hz), 6.63 (1H, br), 6.69 (1H, d, J=8 Hz), 7.18 (1H, d,J=8 Hz), 7.43 (2H, m), 8.17 (1H, dd, J=4, 8 Hz), 8.35 (1H, d, J=4 Hz),8.85 (1H, br).

[1215] Preparation 129(1)

[1216] Methyl 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoate(20.4 g)was obtained as yellow powders from methyl 2-fluoro-5-nitrobenzoate(15.0 g) and trans-4-aminocyclohexanol (13.0 g) in a manner similar toExample 1(1).

[1217] NMR (CDCl₃, δ): 1.36-1.57 (4H, m), 1.97-2.25 (4H, m), 3.43-3.56(1H, m), 3.70-3.84 (1H, m), 3.90 (3H, s), 6.69 (1H, d, J=8 Hz), 8.19(1H, dd, J=2, 8 Hz), 8.60 (1H, br d, J=8 Hz), 8.87 (1H, d, J=2 Hz)

[1218] Mass m/z: 294.(EI+).

[1219] Preparation 129 (2)

[1220] Methyl 2-(cis-4-acetoxycyclohexylamino)-5-nitrobenzo ate (14.6 g)was obtained as yellow powders from methyl2-(trans4-hydroxycyclohexylamino)-5-nitrobenzoate (20.0 g) in a mannersimilar to Example 52(2).

[1221] NMR (DMSO-d₆, δ): 1.56-1.92 (8H, m), 2.04 (3H, s), 3.74-3.86 (1H,m), 3.89 (3H, s), 4.85 (1H, br), 7.05 (1H, d, J=8 Hz), 8.20 (1H, dd,J=2, 8 Hz), 8.64-8.73 (2H, m).

[1222] Preparation 129(3)

[1223] 2-(cis-4-Hydroxycyclohexylamino)-5-nitrobenzoic acid (11.7 g) wasobtained as yellow powders from methyl2-(cis-4-acetoxycyclohexylamino)-5-nitrobenzoate (14.4 g) in a mannersimilar to Example 52(3).

[1224] NMR (DMSO-d₆, δ): 1.45-1.84 (8H, m), 3.62-3.81 (2H, m), 4.57 (1H,br), 6.95 (1H, d, J=8 Hz), 8.15 (1H, dd, J=2, 8 Hz), 8.66 (1H, d, J=2Hz), 8.99 (1H, d, J=8 Hz)

[1225] Mass m/z: 279.1 (M⁺−1).

[1226] Preparation 129(4)

[1227] To a mixture of 3-methoxy-4-nitrobenzyl alcohol (3.00 g) andcarbon tetrabromide (8.15 g) in dichloromethane (60 mL) was addedtriphenylphosphine (5.16 g) under ice-water cooling, and the mixture wasstirred for an hour at ambient temperature. After evaporation of thesolvent, the residue was purified by a silica gel column chromatographyeluting with a mixture of hexane and ethyl acetate (5:1) to give3-methoxy-4-nitrobenzyl bromide as pale yellow powders (4.87 g).

[1228] NMR (CDCl₃, δ): 3.99 (3H, s), 4.47 (2H, s), 7.04 (1H, d, J=8 Hz),7.10 (1H, s), 7.83 (1H, d, J=8 Hz).

[1229] Preparation 129(5) N-(3-Methoxy-4-nitrobenzyl)phthalimide (4.49g) was obtained as colorless powders from 3-methoxy-4-nitrobenzylbromide(4.00 g) and potassium phthalimide (3.31 g) in a manner similar toPreparation 91(3).

[1230] NMR (CDCl₃, δ): 3.97 (3H, s), 4.87 (2H, s), 7.07 (1H, d, J=8 Hz),7.18 (1H, s), 7.72-7.80 (2H, m), 7.81 (1H, d, J=8 Hz), 7.83-7.91 (2H,m). Preparation 129 (6) 3-Methoxy-4-nitrobenzylamine (1.28 g) wasobtained as yellow oil from N-(3-methoxy-4-nitrobenzyl)phthalimide (3.00g) in a manner similar to Preparation 91(4).

[1231] NMR (CDCl₃, δ): 3.97 (2H, s), 3.98 (3H, s), 6.95 (1H, d, J=8 Hz),7. 10 (1H, s), 7.84 (1H, d, J=8 Hz).

EXAMPLE 129

[1232] 2-(cis-4-Hydroxycyclohexylamino)-N-(3-methoxy-4-nitrobenzyl)-5-nitrobenzamide (110 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and3-methoxy-4-nitrobenzylamine (78.0 mg) in a manner similar toPreparation 1.

[1233] NMR (DMSO-d₆, δ): 1.44-1.75 (8H, br), 3.66 (2H, br), 3.93 (3H,s), 4.54 (3H, br), 6.90 (1H, d, J=8 Hz), 7.06 (1H, d, J=8 Hz), 7.34 (1H,s), 7.88 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.69 (1H, d, J=4Hz), 9.27 (1H, br), 9.49 (1H, br)

[1234] Mass m/z: 443 (M⁺).

[1235] Preparation 130(1)

[1236] N-(2-Chloro-5-methoxybenzyl)phthalimide (7.69 g) was obtained ascolorless powders from 2-chloro-5-methoxybenzyl bromide (8.30 g) andpotassium phthalimide (6.85 g) in a manner similar to Preparation 91(3).

[1237] NMR (CDCl₃, δ): 3.73 (3H, s), 4.95 (2H, s), 6.75 (2H, m), 7.27(1H, m), 7.75 (2H, m), 7.88 (2H, m).

[1238] Preparation 130(2)

[1239] 2-Chloro-5-methoxybenzylamine (1.67 g) was obtained as yellow oilfrom N-(2-chloro-5-methoxybenzyl)phthalimide (3.00 g) in a mannersimilar to Preparation 91(4).

[1240] NMR (CDCl₃, δ): 3.80 (3H, s), 3.89 (2H, s), 6.73 (1H, dd, J=4, 8Hz), 6.94 (1H, d, J=4 Hz), 7.25 (1H, d, J=8 Hz).

EXAMPLE 130

[1241]N-(2-Chloro-5-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(125 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and2-chloro-5-methoxybenzylamine (73.5 mg) in a manner similar toPreparation 1.

[1242] NMR (DMSO-d₆, δ): 1.45-1.75 (8H, br), 3.61-3.72 (2H, br), 3.74(3H, s), 4.48 (2H, d, J=7 Hz), 4.53 (1H, d, J=4 Hz), 6.88-6.93 (3H, m),7.39 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.67 (1H, d, J=4 Hz),9.17 (1H, d, J=8 Hz), 9.36 (1H, br)

[1243] Mass m/z: 432 (M⁺).

[1244] Preparation 131(1)

[1245] To a solution of 3-hydroxy-4-methoxybenzoic acid (10.0 g) inmethanol (100 mL) was added conc. sulfuric acid (10 mL) under ice-watercooling, and the mixture was heated for 15 hours under reflux. Afterevaporation of the solvent, the residue was partitioned between ethylacetate and water. The separated organic layer was washed with anaqueous saturated sodium bicarbonate solution, water and brine. Theresultant was dried over magnesium sulfate and evaporated in vacuo togive methyl 3-hydroxy-4-methoxybenzoate as a brown oil (9.43 g).

[1246] NMR (CDCl₃, δ): 3.88 (3H, s), 3.95 (3H, s), 5.69 (1H, s), 6.87(1H, d, J=8 Hz), 7.57-7.64 (2H, m). Preparation 131(2) To a mixture ofmethyl 3-hydroxy-4-methoxybenzoate (4.00 g) and potassium carbonate(4.55 g) in dimethylformamide (20 mL) was added ethyl iodide (2.63 mL)under water-cooling and the mixture was stirred for 2 hours at ambienttemperature. The mixture was partitioned between water and ethylacetate. The separated organic layer was washed with water and brine,dried over magnesium sulfate and evaporated in vacuo to give methyl3-ethoxy-4-methoxybenzoate as pale brown powders (4.55 g).

[1247] NMR (CDCl₃, δ): 1.49 (3H, t, J=7 Hz), 3.89 (3H, s), 3.93 (3H, s),4.16 (2H, q, J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.54 (1H, d, J=4 Hz), 7.66(1H, dd, J=4, 8 Hz).

[1248] Preparation 131(3)

[1249] A mixture of methyl 3-ethoxy-4-methoxybenzoate (4.42 g), methanol(160 mL) and 1N-sodium hydroxide solution (40 mL) was heated for 2 hoursunder reflux. The reaction mixture was acidified with IN-hydrochloricacid to pH 4, and the organic solvent was removed by evaporation. Theaqueous layer was diluted with water and extracted with ethyl acetate.The extract was washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with hexane to give3-ethoxy-4-methoxybenzoic acid as colorless powders (3.76 g).

[1250] NMR (CDCl₃, δ): 1.50 (3H, t, J=7 Hz), 3.95 (3H, s), 4.17 (2H, q,J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.60 (1H, d, J=4 Hz), 7.76 (1H, dd, J=4,8 Hz)

[1251] Mass m/z: 195 (M⁺).

[1252] Preparation 131(4)

[1253] To a mixture of 3-ethoxy-4-methoxybenzoic acid (3.66 g) andoxalyl chloride (2.12 mL) in dichloromethane (40 mL) was addeddimethylformamide (5 drops), and the mixture was stirred for 2 hours atambient temperature. After evaporation of the solvent, the residue wasredissolved in dichloromethane (40 mL). The solution was added to amixture of 28% ammonia solution (40 mL) and dichloromethane (40 mL)under ice-water cooling. The mixture was stirred for an hour at ambienttemperature. The resulting precipitates were collected by filtration andwashed with water and diethyl ether to give 3-ethoxy-4-methoxybenzamideas colorless powders (3.40 g).

[1254] NMR (DMSO-d₆, δ): 1.34 (3H, t, J=7 Hz), 3.80 (3H, s), 4.04 (2H,q, J=7 Hz), 7.00 (1H, d, 3=8 Hz), 7.18 (1H, br), 7.39-7.51 (2H, m), 7.83(1H, br).

[1255] Preparation 131(5)

[1256] To a solution of 3-ethoxy-4-methoxybenzamide (3.30 g) in pyridine(33 mL) was added phosphorus oxychloride (1.73 mL) under ice-watercooling, and the mixture was stirred for 2 hours at ambient temperature.After evaporation of the solvent, the residue was partitioned betweenethyl acetate and water under ice-water cooling. The separated organiclayer was washed with 1N-hydrochloric acid, water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified by asilica gel column chromatography eluting with a mixture of hexare andethyl acetate (5:1 to 4:1) to give 3-ethoxy-4-methoxybenzonitrile ascolorless powders (2.83 g).

[1257] NMR (CDCl₃, δ): 1.49 (3H, t, J=7 Hz), 3.93 (3H, s), 4.10 (2H, q,J=7 Hz), 6.90 (1H, d, J=8 Hz), 7.08 (1H, d, J=4 Hz), 7.27 (1H, dd, J=4,8 Hz).

[1258] Preparation 131(6)

[1259] To a suspension of lithium aluminum hydride (1.17 g) in anhydroustetrahydrofuran (15 mL) was added a solution of3-ethoxy-4-methoxybenzonitrile (2.73 g) in tetrahydrofuran (15 mL). Themixture was stirred for an hour under water cooling and then for an hourat ambient temperature. Potassium sodium (+)-tartrate aqueous solutionwas added to the mixture under ice-water cooling. The mixture wasdiluted with ethyl acetate and the insolubles were filtered off. Afterevaporation of the filtrate, ethyl acetate was added. The solution wasdried over magnesium sulfate and evaporated in vacuo to give3-ethoxy-4-methoxybenzylamine as yellow oil (2.81 g).

[1260] NMR (CDCl₃, δ): 1.47 (3H, t, J=7 Hz), 3.80 (2H, s), 3.87 (3H, s),4.12 (2H, q, J=7 Hz), 6.80-6.90 (3H, m).

EXAMPLE 131

[1261]N-(3-Ethoxy-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(130 mg) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoi c acid (100 mg) and3-ethoxy-4-methoxybenzylamine (77.6 mg) in a manner similar toPreparation 1.

[1262] NMR (DMSO-d₆, δ): 1.32 (3H, t, J=7 Hz), 1.45-1.80 (8H, br),3.60-3.75 (2H, br), 3.73 (3H, s), 3.99 (2H, q, J=7 Hz), 4.37 (2H, d, J=7Hz), 4.55 (1H, d, J=4 Hz), 6.82-6.96 (4H, m), 8.10 (1H, dd, J=4, 8 Hz),8.60 (1H, d, J=4 Hz), 9.24 (1H, d, J=8 Hz), 9.32 (1H, br)

[1263] Mass m/z: 442(M⁺).

[1264] Preparation 132(1)

[1265] 4-Chloro-3-ethoxytoluene (6.08 g) was obtained as pale yellow oilfrom 2-chloro-5-methylphenol (5.00 g) and ethyl iodide (4.21 mL) in amanner similar to Preparation 91 (1).

[1266] NMR (CDCl₃, δ): 1.46 (3H, t, J=7 Hz), 2.32 (3H, s), 4.09 (2H, q,J=7 Hz), 6.66-6.73 (2H, m), 7.22 (1H, d, J=8 Hz).

[1267] Preparation 132(2)

[1268] 4-Chloro-3-ethoxybenzyl bromide (8.75 g) was obtained as yellowoil from 4-chloro-3-ethoxytoluene (6.00 g) in a manner similar toPreparation 91(2).

[1269] NMR (CDCl₃, δ): 1.48 (3H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.44(2H, s), 6.84-6.95 (2H, m), 7.30 (1H, d, J=8 Hz).

[1270] Preparation 132(3)

[1271] N-(4-Chloro-3-ethoxybenzyl)phthalimide (7.88 g) was obtained ascolorless powders from 4-chloro-3-ethoxybenzyl bromide (8.75 g) andpotassium phthalimide (6.82 g) in a manner similar to Preparation 91(3).

[1272] NMR (CDCl₃, δ): 1.46 (3H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz),4.78(2H, s), 6.95 (1H, d, J=8 Hz), 7.04 (1H, s), 7.27 (1H, d, J=8 Hz),7.72 (2H, m), 7.85 (2H, m).

[1273] Preparation 132(4)

[1274] 4-Chloro-3-ethoxybenzylamine (2.25 g) was,obtained as yellow oilfrom N-(4-chloro-3-ethoxybenzyl)phthalimide (4.00 g) in a manner similarto Preparation 91(4).

[1275] NMR (CDCl₃, δ): 1.48 (3H, t, J=7 Hz), 3.82 (2H, s), 4.12 (2H, q,J=7 Hz), 6.79 (1H, d, J=8 Hz), 6.90 (1H, s), 7.25 (1H, d, J=8 Hz).

EXAMPLE 132

[1276] N-(4-Chloro-3-ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide (130 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and4-chloro-3-ethoxybenzylamine (79.5 mg) in a manner similar toPreparation 1.

[1277] NMR (DMSO-d₆, δ): 1.36 (3H, t, J=7 Hz), 1.45-1.80 (8H, br),3.58-3.65 (2H, br), 4.11 (2H, q, J=7 Hz), 4.44 (2H, d, J=7 Hz), 4.56(1H, d, J=4 Hz), 6.86-6.92 (2H, m), 7.12 (1H, s), 7.38 (1H, d, J=8 Hz),8.12 (1H, dd, J=4, 8 Hz), 8.64 (1H, d, J=4 Hz), 9.25 (1H, d, J=8 Hz),9.40 (1H, br)

[1278] Mass m/z: 446 (M⁺).

[1279] Preparation 133(1)

[1280] Methyl 4-hydroxy-3-methoxybenzoate (25.2 g) was obtained ascolorless powders from 4-hydroxy-3-methoxybenzoic acid (25.9 g) in amanner similar to Preparation 131 (1).

[1281] NMR (CDCl₃, δ): 3.89 (3H, s), 3.94 (3H, s), 6.07 (1H, s), 6.94(1H, d, J=8 Hz), 7.55 (1H, s), 7.64 (1H, d, J=8 Hz).

[1282] Preparation 133(2)

[1283] Methyl 4-ethoxy-3-methoxybenzoate (4.10 g) was obtained ascolorless powders from methyl 4-hydroxy-3-methoxybenzoate (4.00 g) andethyl iodide (2.63 mL) in a manner similar to Preparation 131(2).

[1284] NMR (CDCl₃, δ): 1.50 (3H, t, J=7 Hz), 3.89 (3H, s), 3.93 (3H, s),4.14 (2H, q, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.54 (1H, d, J=4 Hz), 7.65(1H, dd, J=4, 8 Hz).

[1285] Preparation 133(3)

[1286] 4-Ethoxy-3-methoxybenzoic acid (3.46 g) was obtained as colorlesspowders from methyl 4-ethoxy-3-methoxybenzoate (3.97 g) in a mannersimilar to Preparation 131(3).

[1287] NMR (CDCl₃, δ): 1.52 (3H, t, J=7 Hz), 3.92 (3H, s), 4.18 (2H, q,J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.58 (1H, s), 7.73 (1H, d, J=8 Hz)

[1288] Mass m/z: 195 (M⁺).

[1289] Preparation 133(4)

[1290] 4-Ethoxy-3-methoxybenzamide (1.74 g) was obtained as colorlesspowders from 4-ethoxy-3-methoxybenzoic acid (3.36 g) in a manner similarto Preparation 131(4).

[1291] NMR (DMSO-d₆, δ): 1.34 (3H, t, J=7 Hz), 3.79 (3H, s), 4.05 (2H,q, J=7 Hz), 6.97 (1H, d, J=8 Hz), 7.19 (1H, br), 7.44-7.49 (2H, m), 7.85(1H, br).

[1292] Preparation 133(5)

[1293] 4-Ethoxy-3-methoxybenzonitrile (1.88 g) was obtained as colorlesspowders from 4-ethoxy-3-methoxybenzamide (2.21 g) in a manner similar toPreparation 131(5).

[1294] NMR (CDCl₃, δ): 1.52 (3H, t, J=7 Hz), 3.89 (3H, s), 4.17 (2H, q,J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.07 (1H, d, J=4 Hz), 7.25 (1H, dd, J=4,8 Hz)

[1295] Mass m/z: 178 (M⁺).

[1296] Preparation 133(6)

[1297] 4-Ethoxy-3-methoxybenzylamine (1.77 g) was obtained as colorlessoil from 4-ethoxy-3-methoxybenzonitrile (1.78 g) in a manner similar toPreparation 131(6).

[1298] NMR (CDCl₃, δ): 1.46 (3H, t, J=7 Hz), 3.81 (2H, s), 3.89 (3H, s),4.09 (2H, q, J=7 Hz), 6.80-6.90 (3H, m).

EXAMPLE 133

[1299]N-(4-Ethoxy-3-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(120 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and4-ethoxy-3-methoxybenzylamine (77.6 mg) in a manner similar toPreparation 1.

[1300] NMR (DMSO-d₆, δ): 1.31 (3H, t, J=7 Hz), 1.43-1.75 (8H, br),3.62-3.72 (2H, br), 3.75 (3H, s), 3.97 (2H, q, J=7 Hz), 4.38 (2H, d, J=7Hz), 4.55 (1H, d, J=4 Hz), 6.81-6.97 (4H, m), 8.11 (1H, dd, J=4, 8 Hz),8.61 (1H, d, J=4 Hz), 9.27 (1H, d, J=8 Hz), 9.32 (1H, br)

[1301] Mass m/z: 442(M⁺).

[1302] Preparation 134(1)

[1303] Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (5.69 g) was obtainedas colorless powders from ethyl 4-hydroxy-3-methoxybenzoate (5.00 g) and2-methoxyethyl bromide (3.59 mL) in a manner similar to Preparation131(2).

[1304] NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 3.46 (3H, s), 3.81 (2H, t,J=4 Hz), 3.91 (3H, s), 4.23 (2H, t, J=4 Hz), 4.35 (2H, q, J=7 Hz), 6.91(1H, d, J=8 Hz), 7.55 (1H, d, J=4 Hz), 7.65 (1H, dd, J=4, 8 Hz).

[1305] Preparation 134(2)

[1306] 3-Methoxy-4-(2-methoxyethoxy)benzoic acid (4.57 g) was obtainedas colorless powders from ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate(5.68 g) in a manner similar to Preparation 131(3).

[1307] NMR (DMSO-d₆, δ): 3.31 (3H, s), 3.68 (2H, t, J=4 Hz), 3.80 (3H,s), 4.15 (2H, t, J=4 Hz), 7.05 (1H, d, J=8 Hz), 7.44 (1H, d, J=4 Hz),7.53 (1H, dd, J=4, 8 Hz)

[1308] Mass m/z: 225 (M⁺).

[1309] Preparation 134(3)

[1310] 3-Methoxy-4-(2-methoxyethoxy)benzamide (3.86 g) was obtained ascolorless powders from 3-methoxy-4-(2-methoxyethoxy)benzoic acid (4.56g) in a manner similar to Preparation 131(4).

[1311] NMR (DMSO-d₆, δ): 3.31 (3H, s), 3.67 (2H, t, J=4 Hz), 3.80 (3H,s), 4.12 (2H, t, J=4 Hz), 7.00 (1H, d, J=8 Hz), 7.21 (1H, br), 7.46 (2H,m), 7.86 (1H, br).

[1312] Preparation 134(4)

[1313] 3-Methoxy-4-(2-methoxyethoxy)benzonitrile (3.21 g) was obtainedas colorless powders from 3-methoxy-4-(2-methoxyethoxy)benzamide (3.66g) in a manner similar to Preparation 131(5).

[1314] NMR (CDCl₃, δ): 3.45 (3H, s), 3.81 (2H, t, J=4 Hz), 3.88 (3H, s),4.20 (2H, t, J=4 Hz), 6.93 (1H, d, J=8 Hz), 7.08 (1H, d, J=4 Hz), 7.25(1H, dd, J=4, 8 Hz).

[1315] Preparation 134(5)

[1316] 3-Methoxy-4-(2-methoxyethoxy)benzylamine (3.26 g) was obtained aspale yellow oil from 3-methoxy-4-(2-methoxyethoxy)benzonitrile (3.11 g)in a manner similar to Preparation 131(6).

[1317] NMR (CDCl₃, δ): 3.45 (3H, s), 3.77 (2H, t, J=4 Hz), 3.79 (2H, s),3.87 (3H, 1H, s), 4.16 (2H, t, J=4 Hz), 6.78-6.92 (3H, m).

EXAMPLE 134

[1318]2-(cis-4-Hydroxycyclohexylamino)-N-[3-methoxy-4-(2-methoxyethoxy)benzyl]-5-nitrobenzamide(150 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-S-nitrobenzoic acid (120 mg) and3-methoxy-4-(2-methoxyethoxy)benzylamine (109 mg) in a manner similar toPreparation 1.

[1319] NMR (DMSO-d₆, δ): 1.45-1.75 (8H, br), 3.30 (3H, s), 3.62 (2H, m),3.60-3.70 (2H, br), 3.75 (3H, s), 4.03 (2H, m), 4.38 (2H, d, J=7 Hz),4.56 (1H, d, J=4 Hz), 6.83-6.98 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.61(1H, d, J=4 Hz), 9.26 (1H, br), 9.32 (1H, br).

[1320] Preparation 135(1)

[1321] Ethyl 4-cyclobutylmethoxy-3-methoxybenzoate (6.32 g) was obtainedas colorless oil from ethyl 4-hydroxy-3-methoxybenzoate (5.00 g) andcyclobutylmethyl bromide (4.30 mL) in a manner similar to Preparation131(2).

[1322] NMR (CDCl₃, δ): 1.41 (3H, t, J=7 Hz), 1.80-2.05 (4H, m),2.13-2.28 (2H, m), 2.78-2.96 (1H, m), 3.91 (3H, s), 4.04 (2H, d, J=7Hz), 4.35 (2H, q, J=7 Hz), 6.87 (1H, d, J=8 Hz), 7.54 (1H, d, J=4 Hz),7.65 (1H, dd, J=4, 8 Hz).

[1323] Preparation 135(2)

[1324] 4-Cyclobutylmethoxy-3-methoxybenzoic acid (5.10 g) was obtainedas colorless powders from ethyl 4-cyclobutylmethoxy-3-methoxybenzoate(6.20 g) in a manner similar to Preparation 131(3).

[1325] NMR (DMSO-d₆, δ): 1.76-1.98 (4H, m), 2.00-2.17 (2H, m), 2.65-2.83(1H, m), 3.80 (3H, s), 4.00 (2H, d, J=7 Hz), 7.04 (1H, d, J=8 Hz), 7.43(1H, d, J=4 Hz), 7.54 (1H, dd, J=4, 8 Hz)

[1326] Mass m/z: 235 (M⁺).

[1327] Preparation 135(3)

[1328] 4-Cyclobutylmethoxy-3-methoxybenzamide (4.50 g) was obtained ascolorless powders from 4-cyclobutylmethoxy-3-methoxybenzoic acid (4.90g) in a manner similar to Preparation 131(4).

[1329] NMR (DMSO-d₆, δ): 1.75-2.00 (4H, m), 2.03-2.17 (2H, m), 2.67-2.80(1H, m), 3.79 (3H, s), 3.98 (2H, d, J=7 Hz), 6.99 (1H, d, J=8 Hz), 7.19(1H, br), 7.43-7.50 (2H, m), 7.85 (1H, br).

[1330] Preparation 135(4)

[1331] 4-Cyclobutylmethoxy-3-methoxybenzonitrile (3.21 g) was obtainedas colorless powders from 4-cyclobutylmethoxy-3-methoxybenzamide (4.35g) in a manner similar to Preparation 131(5).

[1332] NMR (DMSO-d₆, δ): 1.80-2.06 (4H, m), 2.12-2.27 (2H, m), 2.78-2.94(1H, m), 3.87 (3H, s), 4.03 (2H, d, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.07(1H, d, J=4 Hz), 7.25 (1H, dd, J=4, 8 Hz).

[1333] Preparation 135(5)

[1334] 4-Cyclobutylmethoxy-3-methoxybenzylamine (3.61 g) was obtained aspale yellow oil from 4-cyclobutylmethoxy-3-methoxybenzonitrile (3.54 g)in a manner similar to Preparation 131(6).

[1335] NMR (CDCl₃, δ):1.80-2.00 (4H, m), 2.10-2.25 (2H, m), 2.76-2.92(1H, m), 3.81 (2H, s), 3.87 (3H, s), 3.98 (2H, d, J=7 Hz), 6.78-6.86(3H, m).

[1336] Preparation 135(6)

[1337] N-(4-Cyclobutylmethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide(3.17 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoicacid (2.33 g) and 4-cyclobutylmethoxy-3-methoxybenzylamine(2.87 g) in amanner similar to Preparation 55.

[1338] NMR (DMSO-d₆, δ): 1.75-1.98 (4H, m), 2.02-2.14 (2H, m), 2.63-2.78(1H, m), 3.75 (3H, s), 3.90 (2H, d, J=7 Hz), 4.42 (2H, d, J=7 Hz),6.83-6.98 (3H, m), 7.63 (1H, t, J=7 Hz), 8.37-8.44 (2H, m), 9.12 (1H,br)

[1339] Mass m/z: 387 (M⁺).

EXAMPLE 135

[1340]N-(4-Cyclobutylmethoxy-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide(123 mg) was obtained as yellow powders fromN-(4-cyclobutylmethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (150mg) and 2-amino-1,3-propanediol (52.8 mg) in a manner similar to Example1(1).

[1341] NMR (DMSO-d₆, δ): 1.75-1.98 (4H, m), 2.00-2.15 (2H, m), 2.65-2.79(1H, m), 3.50-3.60 (4H, br), 3.60-3.70 (1H, br), 3.74 (3H, s), 3.89 (2H,d, J=7 Hz), 4.36 (2H, d, J=7 Hz), 4.93 (2H, t, J=7 Hz), 6.83 (1H, dd,J=4, 8 Hz), 6.89-7.00 (3H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.57 (1H, d,J=4 Hz), 9.21 (1H, d, J=8 Hz), 9.27 (1H, br).

EXAMPLE 136

[1342] A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid(120 mg), cyclohexanemethylamine (53.3 mg),1-13-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (107 mg)and 1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3mL) was stirred for 18 hours at ambient temperature. The mixture waspartitioned between water and ethyl acetate. The separated organic layerwas washed with 1N-hydrochloric acid, water, an aqueous saturated sodiumbicarbonate solution and brine, successively, and dried over magnesiumsulfate. After evaporation of the solvent, the residue was trituratedwith diisopropyl ether to giveN-cyclohexylmethyl-2-(cis4-hydroxycyclohexylamino)-5-nitrobenzamide (157mg) as yellow powders.

[1343] NMR (DMSO-d₆, δ): 0.83-1.04 (2H, m), 1.04-1.31 (3H, m), 1.40-1.82(14H, m), 3.09 (2H, t, J=7 Hz), 3.65 (2H, br), 4.55 (1H, d, J=4 Hz),6.86 (1H, d, J=8 Hz), 8.10 (1H, dd, J=2, 8 Hz), 8.55 (1H, d, J=2 Hz),8.83 (1H, m), 9.25 (1H, d, J=8 Hz)

[1344] Mass m/z: 374.3 (M⁺−1).

EXAMPLE 137

[1345]2-(cis-4-Hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5-nitrobenzamide(165 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and1-naphthalenemethylamine (74.0 mg) in a manner similar to Example 136.

[1346] NMR (DMSO-d₆, δ): 1.45-1.80 (8H, m), 3.67 (2H, br), 4.58 (1H, d,J=4 Hz), 4.94 (2H, d, J=5 Hz), 6.89 (1H, d, J=8 Hz), 7.45-7.66 (4H, m),7.84-7.93 (1H, m), 7.97 (1H, dd, J=2, 8 Hz), 8.11 (1H, dd, J=2, 9 Hz),8.17 (1H, d, J=8 Hz), 8.61 (1H, d, J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.43(1H, m)

[1347] Mass m/z: 418.2 (M⁺−1).

EXAMPLE 138

[1348]2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(2-quinolinylmethyl)benzamide(53.0 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and2-aminomethylqunoline (62.1 mg) in a manner similar to Example 136.

[1349] NMR (DMSO-d₆, δ): 1.39-1.76 (8H, m), 3.65 (2H, br), 4.51 (1H, d,J=4 Hz), 4.74 (2H, d, J=5 Hz), 6.93 (1H, d, J=8 Hz), 7.52-7.64 (2H, m),7.76 (1H, t, J=8 Hz), 7.95-8.04 (2H, m), 8.14 (1H, dd, J=2, 8 Hz), 8.37(1H, d, J=8 Hz), 8.78 (1H, d, J=2 Hz), 9.25 (1H, d, J=8 Hz), 9.63 (1H,m)

[1350] Mass m/z: 419.2 (M⁺−1).

EXAMPLE 139

[1351] 2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(1(S)-1-phenylethyl]benzamide (123 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and(S)-1-phenylethylamine (62.3 mg) in a manner similar to Example 136.

[1352] NMR (DMSO-d₆, δ): 1.41-1.72 (11H, m), 3.65 (2H, br), 4.53 (1H, d,J=4 Hz), 5.10-5.24 (1H, m), 6.87 (1H, d, J=8 Hz), 7.19-7.30 (1H, m),7.30-7.45 (4H, m), 8.12 (1H, dd, J=2, 8 Hz), 8.71 (1H, d, J=2 Hz),9.10-9.23 (2H, m)

[1353] Mass m/z: 382.2 (M⁺−1).

[1354] Preparation 140(1)

[1355] To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g) inethanol (15 mL) was added a solution of sodium cyamide (461 mg) in water(15 mL) at ambient temperature, and the mixture was heated for 3 hoursunder reflux . After evaporation of the organic solvent, the aqueouslayer was extracted with ethyl acetate. The extract was washed withwater and brine, dried over magnesium sulfate and evaporated in vacuo togive [2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.

[1356] NMR (CDCl₃, δ): 3.97 (2H, s), 7.48 (1H, t, J=8 Hz), 7.62 (1H, t,J=8 Hz), 7.66-7.75 (2H, m).

[1357] Preparation 140(2)

[1358] 2-12-(Trifluoromethyl)phenyl]ethylamine hydrochloride (187 mg)was obtained as pale yellow powders from[2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) in a manner similar toPreparation 131(6).

[1359] NMR (DMSO-d₆, δ): 2.94-3.15 (4H, m), 7.44-7.59 (2H, m), 7.62-7.79(2H, m), 8.16 (2H, br).

EXAMPLE 140

[1360] A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid(120 mg), [2-(trifluoromethyl)phenyl]ethylamine hydrochloride (111 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (86.4 mg) and1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3 mL)was stirred for 18 hours at ambient temperature. The mixture waspartitioned between water and ethyl acetate. The separated organic layerwas washed with 1N-hydrochloric acid, water, an aqueous saturated sodiumbicarbonate solution and brine, successively, and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified by apreparative silica gel thin layer chromatography with a mixture ofhexane and ethyl acetate (2:1). The obtained product was recrystallizedfrom a mixture of petroleum ether and diethyl ether to give2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-{[2-(trifluoromethyl)phenyl]ethyl}benzamide(157 mg) as yellow powders.

[1361] NMR (DMSO-d₆, δ): 1.44-1.75 (8H, m), 3.03 (2H, t, J=7.5 Hz), 3.51(2H, q, J=7.5 Hz), 3.66 (2H, br), 4.56 (1H, d, J=4 Hz), 6.87 (1H, d, J=8Hz), 7.41-7.55 (2H, m), 7.64 (1H, t, J=8 Hz), 7.71 (1H, d, J=8 Hz), 8.11(1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz), 9.00 (1H, m), 9.14 (1H, d, J=8Hz)

[1362] Mass m/z 450.2 (M⁺−H).

[1363] Preparation 141(1)

[1364] 4-Bromomethylthiazole (1.80 g) was obtained as an oil from4-methylthiazole (1.00 g) and N-bromosuccinimide (1.97 g) in a mannersimilar to Preparation 91(2).

[1365] NMR (DMSO-d₆, δ): 4.65 (2H, s), 7.37 (1H, d, J=2 Hz), 8.82 (1H,d, J=2 Hz).

[1366] Preparation 141(2)

[1367] N-(Thiazol-4-ylmethyl)phthalimide (1.20 g) was obtained as whitepowders from 4-bromomethylthiazole (1.80 g) and potassium phthalimide(1.87 g) in a manner similar to Preparation 91(3).

[1368] NMR (DMSO-d₆, δ): 5.06 (2H, s), 7.30 (1H, d, J=2 Hz), 7.68-7.80(2H, in), 7.84-7.92 (2H, m), 8.76 (1H, d, J=2 Hz).

[1369] Preparation 141(3)

[1370] 4-Aminomethylthiazole hydrochloride (305 mg) was obtained aswhite powders from N-(thiazol-4-ylmethyl)phthalimide (1.15 g) in amanner similar to Preparation 91(4).

[1371] NMR (DMSO-d₆, ): 4.18 (2H, q, J=5 Hz), 7.83 (1H, d, J=2 Hz), 8.52(3H, br), 9.20 (1H, d, J=2 Hz).

EXAMPLE 141

[1372]2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(4-thiazolylmethyl)benzamide(92 mg) was obtained as yellow powders from2-(cis4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and4-aminomethylthiazole hydrochloride (70.9 mg) in a manner similar toPreparation 1.

[1373] NMR (DMSO-d₆, δ): 1.42-1.76 (8H, m), 3.65 (2H, br), 4.54 (1H, d,J=4 Hz), 4.59 (1H, d, J=5 Hz), 6.89 (1H, d, J=8 Hz), 7.52 (1H, d, J=2Hz), 8.12 (1H, dd, J=2, 8 Hz), 8.66 (1H, d, J=2 Hz), 9.07 (1H, d, J=2Hz), 9.28 (1H, d, J=8 Hz), 9.45 (1H, m)

[1374] Mass m/z: 375.2 (M⁺-H).

[1375] Preparation 142(1)

[1376] 2-Cyanobenzo[b]thiophene (250 mg) was obtained as an oil frombenzo[b]thiophene-2-carboxamide (500 mg) in a manner similar to

[1377] Preparation 131(5).

[1378] NMR (CDCl₃, δ): 7.48 (1H, t, J=8 Hz), 7.54 (1H, t, J=8 Hz),7.84-7.94 (3H, m).

[1379] Preparation 142(2)

[1380] 2-(Aminomethyl)benzo[b]thiophene hydrochloride (281 mg) wasobtained as pale yellow powders from 2-cyanobenzo[b]thiophene (250 mg)in a manner similar to Preparation 131(6).

[1381] NMR (DMSO-d₆, δ): 4.35 (2H, s), 7.34-7.45 (2H, m), 7.57 (1H, s),7.83-7.90 (1H, m), 7.96-8.04 (1H, m), 8.67 (3H, br).

EXAMPLE 142

[1382]N-(Benzo[b]thiophen-2-ylmethyl)-2-(cis4-hydroxycyclohexylamino)-5-nitrobenzamide(104 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and2-(aminomethyl)benzo[b]thiophene hydrochloride (78.4 mg) in a mannersimilar to Example 140.

[1383] NMR (DMSO-d₆, δ): 1.44-1.80 (8H, m), 3.66 (2H, br), 4.57 (1H, d,J=4 Hz), 4.72 (2H, d, J=5 Hz), 6.91 (1H, d, J=8 Hz), 7.24-7.28 (3H, m),7.79 (1H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz), 8.13 (1H, dd, J=2, 8 Hz),8.64 (1H, d, J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.62 (1H, m).

[1384] Preparation 143(1)

[1385] 2-Cyanobenzofuran (402 mg) was obtained as an oil frombenzofuran-2-carboxamide (500 mg) in a manner similar to Preparation131(5).

[1386] NMR (CDCl₃, δ): 7.37 (1H, t, J=8 Hz), 7.43-7.60 (3H, m), 7.69(1H, d, J=8 Hz).

[1387] Preparation 143(2)

[1388] 2-(Aminomethyl)benzofuran hydrochloride (333 mg) was obtained aspale yellow powders from 2-cyanobenzofuran (400 mg) in a manner similarto Preparation 131(6).

[1389] NMR (DMSO-d₆, δ): 4.23 (2H, s), 7.03 (1H, s), 7.28 (1H, t, J=8Hz), 7.35 (1H, t, J=8 Hz), 7.60 (1H, d, J=8 Hz), 7.69 (1H, d, J=8 Hz),8.62 (3H, br).

EXAMPLE 143

[1390]N-(Benzofuran-2-ylmethyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(154 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and2-(aminomethyl)benzofuran hydrochloride (86.5 mg) in a manner similar toExample 140.

[1391] NMR (DMSO-d₆, δ): 1.43-1.77 (8H, m), 3.67 (2H, br), 4.55 (1H, d,J=4 Hz), 4.63 (2H, d, J=5 Hz), 6.81 (1H, s), 6.90 (1H, d, J=8 Hz), 7.22(1H, t, J=8 Hz), 7.27 (1H, t, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.60 (1H,d, J=8 Hz), 8.11 (1H, dd, J=2, 8 Hz), 8.67 (1H, d, J=2 Hz), 9.30 (1H, d,J=8 Hz), 9.49 (1H, m).

EXAMPLE 144

[1392]N-(3,4-Dimethylbenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide(185 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexyl)amino-5-nitrobenzoic acid (200 mg) and3,4-dimethylbenzylamine (116 mg) in a manner similar to Preparation 1.

[1393] m.p. 157-158° C.

[1394] NMR (DMSO-d₆, δ): 1.34-1.74 (8H, m), 2.19 (3H, s), 2.21 (3H, s),3.60-3.72 (2H, m), 4.38 (2H, d, J=5 Hz), 4.55 (1H, d, J=4 Hz), 6.88 (1H,d, J=10 Hz), 7.04 (1H, br d, J=8 Hz), 7.07-7.14 (2H, m), 8.11 (1H, dd,J=10, 3 Hz), 8.62 (1H, d, J=3 Hz), 9.30 (1H, d, J=8 Hz), 9.34 (1H, t,J=5 Hz)

[1395] Mass m/z: 396(M⁺).

EXAMPLE 145

[1396]2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(4-phenylbenzyl)benzamide(113 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexyl)amino-5-nitrobenzoic acid (78 mg) and4-phenylbenzylamine (61 mg) in a manner similar to Preparation 1.

[1397] m.p. 168-170° C.

[1398] NMR (DMSO-d₆, δ): 1.43-1.80 (8H, m), 3.59-3.75 (2H, m), 4.50 (2H,d, J=6 Hz), 4.55 (1H, d, J=5 Hz), 6.90 (1H, d, J=10 Hz), 7.35 (1H, dd,J=7.5, 7.5 Hz), 7.39-7.52 (4H, m), 7.65 (4H, m), 8.12 (1H, dd, J=10, 2Hz), 8.67 (1H, d, J=2 Hz), 9.33 (1H, d, J=8 Hz), 9.45 (1H, t, J=6 Hz).

[1399] Preparation 146(1)

[1400] Methyl 3-benzyloxy-4-methoxybenzoate (5.70 g) was obtained ascolorless powders from methyl 3-hydroxy-4-methoxybenzoate (4.00 g) andbenzyl bromide (3.13 mL) in a manner similar to Preparation 131(2).

[1401] NMR (CDCl₃, δ): 3.87 (3H, s), 3.93 (3H, s), 5.18 (2H, s), 6.90(1H, d, J=8 Hz), 7.28-7.40 (3H, m), 7.46 (2H, m), 7.61 (1H, d, J=4 Hz),7.68 (1H, dd, J=4, 8 Hz).

[1402] Preparation 146(2)

[1403] 3-Benzyloxy-4-methoxybenzoic acid (5.06 g) was obtained ascolorless powders from methyl 3-benzyloxy-4-methoxybenzoate (5.60 g) ina manner similar to Preparation 131(3).

[1404] NMR (DMSO-d₆, δ): 3.84 (3H, s), 5.13 (2H, s), 7.07 (1H, d, J=8Hz), 7.30-7.50 (5H, m), 7.53 (1H, d, J=4 Hz), 7.58 (1H, dd, J=4, 8 Hz).

[1405] Preparation 146(3)

[1406] 3-Benzyloxy-4-methox>ybenzamide (4.03 g) was obtained ascolorless powders from 3-benzyloxy-4-methoxybenzoic acid (4.96 g) in amanner similar to Preparation 131(4).

[1407] NMR (DMSO-d₆, δ): 3.81 (3H, s), 5.11 (2H, s), 7.02 (1H, d, J=8Hz), 7.21 (1H, br), 7.32-7.47 (5H, m), 7.51 (1H, dd, J=4, 8 Hz), 7.58(1H, d, J=4 Hz), 7.85 (1H, br).

[1408] Preparation 146(4)

[1409] 3-Benzyloxy-4-methoxybenzonitrile (3.35 g) was obtained ascolorless powders from 3-benzyloxy-4-methoxybenzamide (3.93 g) in amanner similar to Preparation 131(5).

[1410] NMR (CDCl₃, δ): 3.94 (3H, s), 5.15 (2H, s), 6.91 (1H, d, J=8 Hz),7.10 (1H, d, J=4 Hz), 7.25-7.45 (6H, m).

[1411] Preparation 146(5)

[1412] 3-Benzyloxy-4-methoxybenzylamine (3.51 g) was obtained as paleyellow oil from 3-benzyloxy-4-methoxybenzonitrile (3.30 g) in a mannersimilar to Preparation 131(6).

[1413] NMR (CDCl₃, δ): 3.76 (2H, s), 3.88 (3H, s), 5.16 (2H, s),6.83-6.90 (3H, m), 7.24-7.45 (5H, m).

EXAMPLE 146

[1414]N-(3-Benzyloxy-4-methoxybenzyl)-2-(cis4-hydroxycyclohexylamino)-5-nitrobenzamide(152 mg) was obtained as yellow powders from2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and3-benzyloxy-4-methoxybenzylamine (104 mg) in a manner similar toPreparation 1.

[1415] NMR (DMSO-d₆, δ): 1.45-1.77 (8H, br), 3.62-3.72 (2H, br), 3.75(3H, s), 4.37 (2H, d, J=7 Hz), 4.56 (1H, d, J=4 Hz), 5.06 (2H, s),6.85-6.97 (3H, m), 7.05 (1H, d, J=2 Hz), 7.24-7.37 (3H, m), 7.40-7.47(2H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.30 (2H, br)

[1416] Mass m/z: 504 (M⁺).

[1417] Preparation 147(1)

[1418] 3,4-Ethylenedioxybenzyl bromide (2.31 g) was obtained ascolorless oil from 3,4-ethylenedioxybenzyl alcohol (2.00 g) and carbontetrabromide (5.99 g) in a manner similar to Preparation 129(4).

[1419] NMR (CDCl₃, δ): 4.25 (4H, s), 4.44 (2H, s), 6.78-6.94 (3H, m).

[1420] Preparation 147(2)

[1421] N-(3,4-Ethylenedioxybenzyl)phthalimide (2.65 g) was obtained aswhite powders from 3,4-ethylenedioxybenzyl bromide (2.31 g) andpotassium phthalimide (1.92 g) in a manner similar to preparation 91(3).

[1422] NMR (CDCl₃, δ): 4.20 (4H, s), 4.64 (2H, s), 6.72-6.81 (3H, m),7.80-7.93 (4H, m)

[1423] Mass m/z: 296.1 (M⁺+1).

[1424] Preparation 147(3)

[1425] 3,4-Ethylenedioxybenzylamine hydrochloride (1.70 g) was obtainedas white powders from N-(3,4-ethylenedioxybenzyl)phthalimide(2.60 g) ina manner similar to Preparation 91(4).

[1426] NMR (DMSO-d₆, δ): 3.88 (2H, q-like), 4.24 (4H, s), 6.84-6.97 (2H,m), 7.03 (1H, d, J=2 Hz), 8.29 (3H, br).

[1427] Preparation 147(4)

[1428] N-(3,4-Ethylenedioxybenzyl)-2-fluoro-5-nitrobenzamide (1.39 g)was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00g) and 3,4-ethylenedioxybenzylamine hydrochloride (1.14 g) in a mannersimilar to Preparation 55.

[1429] NMR (DMSO-d₆, δ): 4.19 (4H, s), 4.34 (1H, d, J=5 Hz), 6.73-6.84(3H, m), 7.59 (1H, t, J=8 Hz), 8.34-8.44 (2H, m), 9.07 (1H, m)

[1430] Mass m/z: 331.4 (M⁺−1).

EXAMPLE 147

[1431]N-(3,4-Ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(496 mg) was obtained as yellow powders fromN-(3,4-ethylenedioxybenzyl)-2-fluoro-5-nitrobenzamide (400 mg) andtrans-4-aminocyclohexanol (208 mg) in a manner similar to Example 1 (1).

[1432] NMR (DMSO-d₆, δ): 1.20-1.43 (4H, m), 1.73-1.88 (2H, m), 1.88-2.05(2H, m), 3.40-3.59 (2H, m), 4.21 (4H, s), 4.30 (2H, d, J=5 Hz), 4.62(1H, d, J=4 Hz), 6.74-6.84 (3H, m), 6.90 (1H, d, J=8 Hz), 8.11 (1H, dd,J=8, 2 Hz), 8.59 (1H, d, J=2 Hz), 9.08 (1H, d, J=8 Hz), 9.30 (1H, m)

[1433] Mass m/z : 426.2 (M⁺−1).

[1434] Preparation 148

[1435]N-(3-Chloro-4-methoxybenzyl)-2-filuoro-5-(trifluoromethyl)benzamide(2.92 g) was obtained from 2-fluoro-5-(trifluoromethyl)benzoic acid(1.76 g) and 3-chloro-4-10 methoxybenzylamine (1.45 g) in a in a mannersimilar to Preparation 1.

[1436] NMR (DMSO-d₆, δ): 3.83 (3H, s), 4.41 (2H, d, J=6 Hz), 7.13 (1H,d, J=9 Hz), 7.29 (1H, dd, J=2, 8 Hz), 7.41 (1H, d, J=2 Hz), 7.58 (1H, t,J=9 Hz), 7.93 (1H, m), 7.97 (1H, d, J=8 Hz), 9.08 (1H, t, J=6 Hz).

EXAMPLE 148

[1437]N-(3-Chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-(trifluoromethyl)benzamide(91 mg) was obtained fromN-(3-chloro-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide (194mg) and 2-amino-1,3-propanediol (147 20 mg) in a manner similar toExample 1(1).

[1438] NMR (DMSO-d₆, δ): 3.4-3.6 (5H, m), 3.83 (3H, s), 4.35 (2H, d, J=6Hz), 4.83 (2H, m), 6.91 (1H, d, J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.26 (1H,dd, J=2, 9 Hz), 7.37 (1H, d, J=2 Hz), 7.53 (1H, dd, J=2, 9 Hz), 7.93(1H, d, J=2 Hz), 8.63 (1H, m), 9.07 (1H, t, J=6 Hz)

[1439] Mass m/z: 431 (M⁺−1).

EXAMPLE 149(1)

[1440](R)-2-1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxybenzyl)-5-(trifluoromethyl)benzamide(696 mg) was obtained 30 as amorphous powders fromN-(3-chloro-4-methoxybenzyl)-2-fluoro-5-trifluoromethylbenzamide (700mg) and (R)-3-amino-1-tert-butoxycarbonylpyrrolidine (721 mg) in amanner similar to Example 1 (1).

[1441] NMR (DMSO-d₆, δ): 1.39 (9H, s), 1.83 (1H, m), 2.20 (1H, m), 3.09(1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.83 (3H, s), 4.15 (1H, m),4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.25(1H, dd, J=2, 8 Hz), 7.36 (1H, d, J=2 Hz), 7.59 (1H, brd, J=8 Hz), 7.98(1H, br), 8.61 (1H, d, J=7 Hz), 9.17 (1H, t, J=6 Hz)

[1442] Mass: (ESI+) 528(M+H), (ESI−) 526(M−H).

EXAMPLE 149(2)

[1443](R)-N-(3-Chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluoromethyl)benzamide(448 mg) was obtained as amorphous powders from(R)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxybenzyl)-5-(trifluoromethyl)benzamide(596 mg) in a manner similar to Example 87(2).

[1444] NMR (DMSO-d₆, δ): 1.49 (1H, m), 2.10 (1H, m), 2.55 (1H, dd, J=4,10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10 Hz), 3.83 (3H, s), 3.93(1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d, J=8 Hz), 7.11 (1H, d, J=8Hz), 7.26 (1H, dd, J=2, 8 Hz), 7.37 (1H, d, J=2 Hz), 7.56 (1H, dd, J=2,8 Hz), 7.95 (1H, d, J=2 Hz), 8.52 (1H, d, J=7 Hz), 9.13 (1H, t, J=6 Hz)

[1445] Mass: (ESI+) 428(M+H), (ESI−) 426(M−H).

EXAMPLE 149(3)

[1446](R)-N-(3-Chloro-4-methoxybenzyl)-2-1-(methoxycarbonyl)pyrrolidin-3-ylamino]-5-trifluoromethylbenzamide (119 mg) was obtained as amorphous powders from(R)-N-(3-chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluoromethyl)benzamide (109 mg) in amanner similar to Example 85(5).

[1447] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.21 (1H, m), 3.16 (1H, m),3.30-3.50 (2H, m), 3.58 and 3.59 (3H, s), 3.66 (1H, m), 3.83 (3H, s),4.18 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=9 Hz), 7.11 (1H, d,J=9 Hz), 7.25 (1H, dd, J=2, 9 Hz), 7.36 (1H, d, J=2 Hz), 7.59 (1H, brd,J=9 Hz), 7.99 (1H, br), 8.62 (1H, d, J=7 Hz), 9.18 (1H, t, J=6 Hz).

EXAMPLE 150 (1)

[1448](S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxybenzyl)-5-(trifluoromethyl)benzamide(516 mg) was obtained as amorphous powders fromN-(3-chloro-4-methoxybenzyl)-2-fluoro-5 trifluoromethylbenzamide (700mg) and (S)-3-amino-1-tert-butoxycarbonylpyrrolidine (721 mg) in amanner similar to Example 1 (1).

[1449] NMR (DMSO-d₆, δ): 1.39 (9H, s), 1.83 (1H, m), 2.20 (1H, m), 3.09(1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.83 (3H, s), 4.15 (1H, m),4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.25(1H, dd, J=2, 8 Hz), 7.36 (1H, d, J=2 Hz), 7.59 (1H, brd, J=8 Hz), 7.98(1H, brs), 8.61 (1H, d, J=7 Hz), 9.17 (1H, t, J=6 Hz).

EXAMPLE 150(2)

[1450](S)-N-(3-Chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluoromethyl)benzamide(262 mg) was obtained as amorphous powders from(S)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxybenzyl)-S-(trifluoromethyl)benzamide(430 mg) in a manner similar to Example 87(2).

[1451] NMR (DMSO-d₆, δ): 1.49 (1H, m), 2.10 (1H, m), 2.55 (1H, dd, J=4,10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10 Hz), 3.83 (3H, s), 3.93(1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d, J=8 Hz), 7.11 (1H, d, J=8Hz), 7.26 (1H, dd, J=2, 8 Hz), 7.37 (1H, d, J=2 Hz), 7.56 (1H, dd, J=2,8 Hz), 7.95 (1H, d, J=2 Hz), 8.52 (1H, d, J=7 Hz), 9.13 (1H, t, J=6 Hz)

[1452] Mass (ESI+) 428(M+H), (ESI−) 426(M−H).

EXAMPLE 150(3)

[1453](S)-N-(3-Chloro-4-methoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylamino]-5-(trifluoromethyl)benzamide(105 mg) was obtained as amorphous powders from(S)-N-(3-chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluoromethyl)benzamide (115 mg) in a manner similar to Example 85(5).

[1454] NMR (DMSO-d₆, δ): 1.86 (1H, m), 2.21 (1H, m), 3.16 (1H, m),3.30-3.50 (2H, m), 3.58 and 3.59 (3H, s), 3.66 (1H, m), 3.83 (3H, s),4.18 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=9 Hz), 7.11 (1H, d,J=9 Hz), 7.25 (1H, dd, J=2, 9 Hz), 7.36 (1H, d, J=2 Hz), 7.59 (1H, brd,J=9 Hz), 7.99 (1H, br), 8.62 (1H, d, J=7 Hz), 9.18 (1H, t, J=6 Hz).

[1455] Preparation 151

[1456] 4-Chloro-2,5-difluoro-N-(3,4-dimethoxybenzyl)benzamide (1.66 g)was obtained from 4-chloro-2,5-difluorobenzoic acid (1.05 g) andveratrylamine (0.91 mL) in a in a manner similar to preparation 1.

[1457] NMR (DMSO-d₆, δ): 3.73 (3H, s), 3.74 (3H, s), 4.39 (2H, d, J=6Hz), 6.81-6.97 (3H, m), 7.67 (1H, dd, J-6, 9 Hz), 7.79 (1H, dd, J=6, 9Hz), 8.96 (1H, t, J=6 Hz).

EXAMPLE 151

[1458]4-Chloro-N-(3,4-dimethoxybenzyl)-5-fluoro-2-(trans4-hydroxycyclohexylamino)benzamide(27 mg) was obtained from4-chloro-2,5-difluoro-N-(3,4-dimethoxybenzyl)benzamide (102 mg) andtrans-4-aminocyclohexanol (103 mg) in a manner similar to Example

[1459] NMR (DMSO-d₆, δ): 1.06-1.39 (4H, m), 1.74-1.84 (2H, m), 1.88-1.97(2H, m), 3.38-3.53 (2H, m), 3.72 (3H, s), 3.73 (3H, s), 4.33 (2H, d, J=6Hz), 4.57 (1H, d, J=4 Hz), 6.80-6.93 (4H, m), 7.66 (1H, d, J=11 Hz),7.83 (1H, d, J=8 Hz), 8.89 (1I, t, 3=6 Hz).

[1460] Preparation 152(1)

[1461] 5-Bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (3.07 g)was obtained as colorless powders from 5-bromo-2-fluorobenzoic acid(2.00 g) and 4-chloro-3-methoxybenzylamine (1.72 g) in a manner similarto Preparation 1.

[1462] NMR (DMSO-d₆, δ): 3.85 (3H, s), 4.45 (2H, d, J=7 Hz), 6.91 (1H,dd, J=4, 258 Hz), 7.13 (1H, d, J=4 Hz), 7.32 (1H, t, J=8 Hz), 7.38 (1H,d, J=8 Hz), 7.69-7.80 (2H, m), 9.05 (1H, br).

[1463] Preparation 152(2)

[1464] To a solution of5-bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (2.00 g) intoluene (40 mL) were added tetrakis(triphenylphosphine)palladium (217mg) and tributylvinyltin (1.87 g), and the mixture was heated for 4hours under reflux. After evaporation of the solvent, the residue waspartitioned between ethyl acetate and saturated potassium fluoridesolution. The remaining precipitates were removed by filtration. Theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified by asilica gel column chromatography eluting with a mixture of hexane andethyl acetate (3:1) to giveN-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide as pale yellowpowders (1.51 g).

[1465] NMR (CDCl₃, δ): 3.90 (3H, s), 4.65 (2H, br), 5.31 (1H, d, J=10Hz), 5.77 (1H, d, J=15 Hz), 6.65-6.78 (1H, dd, J=10, 15 Hz), 6.84-6.94(2H, br), 6.96-7.10 (2H, m), 7.33 (1H, d, J=8 Hz), 7.50 (1H, m), 8.12(1H, dd, J=4, 8 Hz)

[1466] Mass m/z: 318 (M⁺).

[1467] Preparation 152(3)

[1468] A mixture of copper(I) chloride (464 mg) and palladium(II)chloride (83.2 mg) in a mixture of dimethylformamide (42 mL) and water(6 mL) was stirred for an hour under oxygen atmosphere (1 atm) atambient temperature. To the mixture was addedN-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide (1.50 g). Afterstirring for 6 hours at 60° C., the mixture was partitioned betweenethyl acetate and IN-hydrochoric acid. The separated organic layer waswashed with water, an aqueous saturated sodium bicarbonate solution andbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by a silica gel column chromatography eluting with amixture of hexane and ethyl acetate (2:1 to 1:1) to give5-acetyl-2-fluoro-N-(4-chloro-3-methoxybenzyl)benzamide as colorlesspowders (719 mg).

[1469] NMR (DMSO-d₆, δ): 2.61 (3H, s), 3.85 (3H, s), 4.48 (2H, d, J=7Hz), 6.94 (1H, dd, J=4, 8 Hz), 7.15 (1H, d, J=4 Hz), 7.39 (1H, d, J=8Hz), 7.47 (1H, t, J=8 Hz), 8.12 (1H, m), 8.19 (1H, dd, J=4, 8 Hz), 9.09(1H, br)

[1470] Mass m/z :334(M⁺).

EXAMPLE 152

[1471] (R)—Acetyl-N-(4-chloro-3-methoxybenzyl)-2(2-hydroxy—methylethylamino)benzamide (68.1 mg) was obtained ascolorless powders from5-acetyl-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (100 mg) and(R)-2-amino-1-propanol (44.7 mg) in a manner similar to Example 1 (1).

[1472] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=7 Hz), 2.47 (3H, s), 3.38-3.50(2H, m), 3.62-3.72 (1H, br), 3.85 (3H, s), 4.43 (2H, d, J=7 Hz), 4.91(1H, t, J=7 Hz), 6.80 (1H, d, J=8 Hz), 6.91 (1H, dd, J=4, 8 Hz), 7.13(1H, d, J=4 Hz), 7.38 (1H, d, J=8 Hz), 7.86 (1H, dd, J=4, 8 Hz), 8.25(1H, d, J-4 Hz), 8.63 (1H, d, J=8 Hz), 9.17 (1H, br).

[1473] Preparation 153(1)

[1474] 5-Chlorosulfonyl-2-fluorobenzoic acid (2 g) was dissolved indichloromethane (20 mL) under nitrogen atmosphere and cooled to 0° C.tert-Butyl 1-piperazinecarboxylate (3.12 g) was added portionwise to thesolution at 0° C. and stirred for 3 hours at ambient temperature. Theorganic solvent was evaporated in vacuo, and the residue was dissolvedin 1N-sodium hydroxide solution. The aqueous solution was washed withdiethyl ether and acidified with 1N-hydrochloric acid. The precipitateswere collected by filtration and washed with water to give5-4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluorobenzoic acid(2.26 g) as a colorless solid substance.

[1475] mp. 203-204.5° C.

[1476] NMR (DMSO-d₆, δ): 1.35 (9H, s), 2.84-3.01 (4H, m), 3.35-3.54 (4H,m), 7.62 (1H, dd, J=9.0, 8.5 Hz), 7.95-8.04 (1H, m), 8.14 (1H, dd,J=7.0, 2.5 Hz)

[1477] Mass m/z: 387 (M⁺−1)

[1478] Preparation 153(2)

[1479]5-[4-(tert-Butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide(1.34 g) was obtained as off-white amorphous substance from5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluorobenzoic acid(1.0 g) and 3,4-dimethoxybenzylamine (452 mg) in a manner similar toPreparation 1.

[1480] NMR (DMSO-d₆, δ): 1.34 (9H, s), 2.85-2.94 (4H, m), 3.36-3.44 (4H,m), 3.73 (3H, s), 3.74 (3H, s), 4.42 (2H, d, J=6.0 Hz), 6.86 (1H, dd,J=8.0, 1.5 Hz), 6.92 (1H, d, J=8.0 Hz), 6.96 (1H, d, J=1.5 Hz), 7.60(1H, t, J=9.0 Hz), 7.85-7.92 (2H, m), 9.04 (1H, t, J=6.0 Hz).

EXAMPLE 153(1)

[1481]5-[4-(tert-Butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)benzamide(191.8 mg) was obtained as off-white solid substance from5-14-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide(200 mg) and trans-4-aminocyclohexanol (129 mg) in a manner similar toExample 1 (1).

[1482] mp. 221-222° C.

[1483] NMR (DMSO-d₆, δ): 1.13-1.41 (4H, m), 1.34 (9H, s), 1.76-1.86(1H,m), 1.90-2.01 (2H, m), 2.77-2.88 (4H, m), 3.30-3.54 (6H, m), 3.72 (3H,s), 3.73 (3H, s), 4.36 (2H, d, J=6.0 Hz), 4.60 (1H, d, J=4.5 Hz), 6.83(1H, d, J=7.5 Hz), 6.89 (1H, s), 6.93 (2H, d, J=7.5 Hz), 7.52 (1H, d,J=7.5 Hz), 7.91 (1H, s), 8.50 (1H, d, J=7.5 Hz), 9.15 (1H, t, J=6.0 Hz)

[1484] Mass m/z: 631 (M⁺−1).

EXAMPLE 153(2)

[1485]N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(piperazinosulfonyl)benzamide(88.3 mg) was obtained as a pale yellow solid substance from5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)benzamide(125 mg) in a manner similar to Example 77(2).

[1486] m.p. 108-110° C.

[1487] NMR (DMSO-d₆, δ): 1.15-1.41 (4H, m), 1.75-1.86 (2H, m), 1.90-2.01(2H, m), 2.65-2.79 (8H, m), 3.29-3.51 (3H, m), 3.72 (3H, s), 3.73 (3H,s), 4.35 (2H, d, J=6.0 Hz), 4.60 (1H, d, J=4.5 Hz), 6.81 (1H, dd, J=8.0,1.0 Hz), 6.90 (2H, d, J=8.0 Hz), 6.94 (1H, d, J=l.OHz), 7.51 (1H, dd,J=8.0, 1.0 Hz), 7.91 (1H, d, J=1.0 Hz), 8.53 (1H, d, J=7.0 Hz), 9.18(1H, t, J=6.0 Hz)

[1488] Mass m/z: 533 (M⁺+1).

EXAMPLE 153(3)

[1489] To a mixture ofN-(3-fluoro-4-methoxybenzyl)-2-(trans4-hydroxycyclohexylamino)-5-nitrobenzamide(262 mg), benzoic acid (115 mg) and diethyl azodicarboxylate (164 mg) inanhydrous tetrahydrofuran (6 mL) was added triphenylphosphine (247 mg).After stirring for one day at ambient temperature, the mixture wasevaporated in vacuo. The residue was purified by a silica gel columnchromatography eluting with a mixture of hexane and ethyl acetate (4:1to 2:1). Collection of an upper fraction gave2-(3-cyclohexenylamino)-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide asyellow powders (40 mg).

[1490] m.p. 140° C.

[1491] NMR (DMSO-d₆, δ): 1.61 (1H, m), 1.82-2.26 (4H, m), 2.45 (1H, m),3.81 (3H, s), 3.85 (1H, m), 4.37 (2H, d, J=5 Hz), 5.64 (1H, br d, J=9Hz), 5.73 (1H, br d, J=9 Hz), 6.94 (1H, d, J=9 Hz), 7.06-7.22 (3H, m),8.12 (1H, dd, J=9, 3 Hz), 8.62 (1H, d, J=3 Hz), 9.19 (1H, d, J=8 Hz),9.35 (1H, t, J=5 Hz)

[1492] Mass m/z (ES): 398.

[1493] Collection of a lower fraction gave2-(cis-4-benzoyloxycyclohexylamino)-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamideas yellow powders (249 mg)

[1494] NMR (DMSO-d₆, δ): 1.60-1.78 (2H, m), 1.80-1.97 (6H, m), 3.75 (1H,m), 3.81 (3H, s), 4.40 (2H, d, J=6 Hz), 5.14 (1H, br), 6.97 (1H, d, J=10Hz), 7.07-7.22 (2H, m), 7.45-7.60 (2H, m), 7.67 (1H, dd, J=7, 7 Hz),8.01 (2xlH, d, J=7 Hz), 8.44 (1H, dd, J=10, 2 Hz), 8.64 (1H, d, J=2 Hz),9.26 (1H, d, J=8 Hz), 9.39 (1H, t, J=6 Hz)

[1495] Mass m/z (ES):520.

[1496] Preparation 154

[1497] N-(4-Chloro-3-methoxybenzoyl)-5-cyano-2-fluorobenzamide (4.00 g)was obtained as colorless powders from 5-cyano-2-fluorobenzoic acid(4.57 g) and 4-chloro-3-methoxybenzylamine (150 mg) in a manner similarto Preparation 1.

[1498] NMR (DMSO-d₆, δ): 3.85 (3H, s), 4.46 (2H, d, J=7 Hz), 6.93 (1H,dd, J=4, 8 Hz), 7.13 (1H, d, J=4 Hz), 7.39 (1H, d, J=8 Hz), 7.58 (1H, t,J=8 Hz), 8.06 (1H, m), 8.13 (1H, dd, J=4, 8 Hz), 9.12 (1H, br).

EXAMPLE 154

[1499](R)-N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(2-hydroxy-1-methylethylamino)benzamide(153 mg) was obtained as colorless powders fromN-(4-chloro-3-methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and(R)-2-amino-1-propanol (70.7 mg) in a manner similar to Example 1(1).

[1500] NMR (DMSO-d₆, δ): 1.12 (3H, d, J=7 Hz), 3.42 (2H, t, J=7 Hz),3.60-3.74 (1H, br), 3.85 (3H, s), 4.41 (2H, d, J=7 Hz), 4.93 (1H, t, J=7Hz), 6.84 (1H, d, J=8 Hz), 6.92 (1H, dd, J=4, 8 Hz), 7.12 (1H, d, J=4Hz), 7.37 (1H, d, J=8 Hz), 7.61 (1H, dd, J=4, 8 Hz), 8.06 (1H, d, J=4Hz), 8.69 (1H, d, J=8 Hz), 9.07 (1H, br)

[1501] Mass m/z: 372.

1. A compound of the formula (I):

wherein R¹ is hydrogen atom or a halogen atom; R² is an electronwithdrawing group; R³ is hydrogen atom; hydroxy group; a lower alkoxygroup; a cycloalkyl group; a substituted or unsubstituted aryl group; oran unsaturated heterocyclic group optionally substituted with loweralkyl; A is a lower alkylene group; R⁴ is a lower alkoxy group, asubstituted or unsubstituted, saturated or unsaturated heterocyclicgroup, an amino group optionally substituted with halo(lower)alkyl orlower alkyl, a group —CH₂—R⁵ wherein R⁵ is a cycloalkyl group or anunsaturated heterocyclic group, or a group —CR⁶R⁷R⁸ wherein R⁶ and R⁷are each independently carboxy group, a protected carboxy group, acarbamoyl group optionally substituted with lower alkyl, or a loweralkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen atom; hydroxy group; cyanogroup; azido group; lower alkoxy group; lower alkylthio group; protectedcarboxy group; lower alkanesulfonyl group; acyloxy group; loweralkanesulfonyloxy group; aryl group; aryloxy group which may besubstituted with cyano; unsaturated heterocyclic group which may besubstituted with lower alkyl; guanidino group which may be substitutedwith lower alkyl, cyano and/or halogen; isothioureido group which may besubstituted with lower alkyl and/or cyano; and amino group which may besubstituted with acyl, protected carboxy, lower alkanesulfonyl, loweralkanesulfonyloxy or aryloxycarbonyl, or R⁶ and R⁷ together with thecarbon atom to which R⁶ and R⁷ are attached may form a substituted orunsubstituted, saturated carbocyclic group, or an unsaturatedcarbocyclic group optionally substituted with hydroxy, and R⁸ ishydrogen atom; a lower alkoxy group; or a lower alkyl group optionallysubstituted with hydroxy or a lower alkoxy; provided that when R⁴ is thegroup —CR⁶R⁷R⁸ wherein R⁶ is a lower alkyl group optionally substitutedwith halogen, R⁷ is a lower alkyl group optionally substituted withhalogen, and R⁸ is hydrogen atom or a lower alkyl group, or when R⁴ isthe group —CH₂—R⁵ wherein R⁵ is the same as the above, R³ should behydrogen atom, hydroxy group or a cycloalkyl group; and a pro-drugthereof, and a salt thereof.
 2. A compound of claim 1, wherein theelectron withdrawing group for R² is selected from a group consisting ofnitro group; cyano group; acyl group; halo(lower)alkyl group; sulfamoylgroup; carbarnoyl group optionally substituted with lower alkyl; halogenatom; lower alkenyl group optionally substituted with protected carboxy;lower alkanesulfonyl group; saturated heterocyclic sulfonyl groupoptionally substituted with protected carboxy; and unsaturatedheterocyclic group, the substituent(s) on the aryl group for R³ is/areselected from a group consisting of lower alkyl group; halo(lower)alkylgroup; lower alkylthio group; halogen atom; hydroxy group; loweralkylenedioxy group; cyano group; nitro group; carboxy group; protectedcarboxy group; sulfarnoyl group; acyl group; aryl group; ar(lower)alkoxygroup; aryloxy group; lower alkoxy group which may be substituted withlower alkoxy or cycloalkyl; amino group which may be substituted withacyl, protected carboxy or lower alkyl and carbamoyl group which may besubstituted with lower alkyl, the substituent(s) on the saturated orunsaturated heterocyclic group for R⁴ is/are selected from a groupconsisting of oxo group; acyl group; protected carboxy group; loweralkanesulfonyl group; sulfamoyl group which may be substituted withprotected carboxy; ar(lower)alkyl group; lower alkyl group which may besubstituted with hydroxy or aryl; ureido group which may be substitutedwith lower alkyl; guanidino group which may be substituted withprotected carboxy; arnidino group which may be substituted withprotected carboxyl; and carbamoyl group which may be substituted withlower alkyl, and the substituent(s) on the saturated carbocyclic groupformed by combination of R⁶ and R⁷ is/are selected from a groupconsisting of lower alkyl group; halogen atom; hydroxy group; loweralkoxy group; acyloxy group; carboxy group; protected carboxy group; oxogroup; amidino group which may be substituted with protected carboxy;ureido group which may be substituted with lower alkyl or aryl;guanidino group which may be substituted with protected carboxy; aminogroup which may be substituted with acyl, lower alkanesulfonyl orprotected carboxy; and carbamoyl group which may be substituted withlower alkyl or hydroxy(lower) alkyl.
 3. A compound of claim 1, whereinR³ is a substituted or unsubstituted aryl group; R⁴ is a group —CR⁶R⁷R⁸wherein R⁶ and R⁷ together with the carbon atom to which R⁶ and R⁷ areattached may form a substituted or unsubstituted, saturated carbocyclicgroup, and R⁸ is hydrogen atom.
 4. A compound of claim 3, wherein R² isnitro group, cyano group or a halo(lower)alkyl group; R³ is an arylgroup optionally substituted with one or more substituent(s) selectedfrom halogen and lower alkoxy; R⁴ is a group —CR⁶R⁷R⁸ wherein R⁶ and R⁷together with the carbon atom to which R⁶ and R⁷ are attached may form asaturated carbocyclic group optionally substituted with hydroxy or aminowhich may be substituted with acyl; and R⁸ is hydrogen atom.
 5. Acompound of claim 4 which isN-(2-chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide,N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,N-(4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,2-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5-nitrobenzamide,2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide,2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl) benzamide,2-(cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide,2-(cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide,N-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,N-(4-bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,2-(cvclopentylamino)-5-nitro-N-phenethylbenzamide,2-(cyclopentylamino)-5-nitro-N-(3-ph enylpropyl)benzamide,N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide,N-benzyl-2-cycloheptylamino-5-nitrobenzamide,N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide,N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-(cyclopentylamino)-N-(2,4-difluoro benzyl)-5-nitrobenzamide,N-benzyl-2-(cyclopropylamino)-5-nitrobenzamide, N-benzyl-2-(2-hydroxycyclohexylamino)-nitrobenzamide,N-benzyl-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide,2-(cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-(trans-2-hydroxycyclopentylarino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,2-(cis-4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,N-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,N-benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide,2-[3-(benzoyloxy)cyclopentylamino]-N-benzyl-5-nitrobenzamide,N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(trans-2-aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,N-(3-chloro-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-[cis4-(benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide,N-(3-chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,N-(3,4-dimethoxybenzyl)-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide,5N-(3,5-dichloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,N-(3,4-ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(3,4,5-trimethoxybenzyl)benzamide,2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,2-(cis-4-hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5-nitrobenzamide,2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl)amino]-5-nitrobenzamide,N-(2-chloro-5-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(cis-4-benzoyloxycyclohexylamino)-N-(3-filuoro-4-methoxybenzyl)-5-nitrobenzamide,N-(3-ethoxy-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,N-(4-chloro-4-ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitro-benzamide,N-(4-ethoxy-3-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitrobenzamide,N-(4-ethoxy-3-methoxybenzyl)-2-(trans4-fonnamidocvclohexylamino)-5-nitrobenzamide,5-cyano-2-(trans-4-hydroxycyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-(cis-4-formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-[(1S)-1-phenylethyl]benzamide,5-bromo-N-(3-chloro-4-methoxybenzyl)-2-(cyclopentylamino)benzamide,5-chloro-2-(cyclopentylamino)-N-(1,3-benzodioxo-5-ylmethyl)benzamide,4-chloro-N-(3,4-dimethoxybenzyl)-5-fluoro-2-(trans-4-hydroxycyclohexylarninc)benzamide,or2-(cis-4-aminocyclohexylamino)-N-(3,4-dirnethoxybenzyl)-5-nitrobenzamide,or a salt thereof.
 6. A compound of claim 1, wherein R³ is a substitutedor unsubstituted aryl group; R⁴ is a group —CR⁶R⁷R⁸ wherein R⁶ is alower alkyl group substituted with hydroxy, R⁷ is a lower alkyl whichmay be substituted with hydroxy, and R⁸ is hydrogen atom or a loweralkyl group which may be substituted with hydroxy.
 7. A compound ofclaim 6, wherein R² is nitro group, cyano group or a halo(lower)alkylgroup; and R³ is an aryl group optionally substituted with one or moresubstituent(s) selected from halogen and lower alkoxy.
 8. A compound ofclaim 7 which isN-benzyl-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,(R)-2(1-ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,(S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,(R)-2-(2-hydroxy-1-methylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-[2-hydroxy-1,1-bis(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-(2-hydroxy-1,1-dimethylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-[2-hydroxy-1-(hydroxymethyl)-1-methylethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,(S)-2-[1-(hydroxymethyl)-2-methylpropylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,2-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,N-(3-chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylamino]-5-nitrobenzamide,2-[1-(hydroxyethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide,(S)-N-(3,4-dimethoxybenzyl)-2-[1-(hydroxymethyl)propylamino]-5-nitrobenzamide,N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1,1-dimethylethylamino)-5-nitrobenzamide,N-(3-fluoro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,N-(4-chloro-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-N-(2-naphthylmethyl)-5-nitrobenzamide,2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide,N-(3-chloro-4-fluorobenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,(S)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide,(S)-N-(3,5-dimethoxybenzyl)-2-(2-hydroxy-1-methylethyl)amino-5-nitrobenzamide,N-(3-chioro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-(trifluoromethyl)benzamide,(R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide,(S)-S-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide,(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide,or(R)-N-(4-chloro-3-methoxybenzyl)-5-cyano-2-(hydroxy-1-methylethylamino)benzamide,or a salt thereof.
 9. A compound of claim 1 for use as a medicament. 10.A process for preparing a compound of the formula:

wherein R¹ is hydrogen atom or a halogen atom; R² is an electronwithdrawing group; R³ is hydrogen atom; hydroxy group; a lower alkoxygroup; a cycloalkyl group; a substituted or unsubstituted aryl group; oran unsaturated heterocyclic group optionally substituted with loweralkyl; A is a lower alkylene group; R⁴ is a lower alkoxy group, asubstituted or unsubstituted, saturated or unsaturated heterocyclicgroup, an amino group optionally substituted with halo(lower)alkyl orlower alky, a group —CH₂—R⁵ wherein R⁵ is a cycloalkyl group or anunsaturated heterocyclic group, or a group —CR⁶R⁷R⁸ wherein R⁶ and R⁷are each independently carboxy group, a protected carboxy group, acarbamoyl group optionally substituted with lower alkyl, or a loweralkyl group optionally substituted with one or more substituentsselected from the group consisting of halogen atom; hydroxy group; cyanogroup; azido group; lower alkoxy group; lower alkylthio group; protectedcarboxy group; lower alkanesulfonyl group; acyloxy group; loweralkanesulfonyloxy group; aryl group; aryloxy group which may besubstituted with cyano; unsaturated heterocyclic group which may besubstituted with lower alkyl; guanidino group which may be substitutedwith lower alky, cyano and/or halogen; isothioureido group which may besubstituted with lower alkyl and/or cyano; and amino group which may besubstituted with acyl, protected carboxy, lower alkanesulfonyl, loweralkanesulfonyloxy or an aryloxycarbonyl, or R⁶ and R⁷ together with thecarbon atom to which R⁶ and R⁷ are attached may form a substituted orunsubstituted, saturated carbocyclic group, or an unsaturatedcarbocyclic group optionally substituted with hydroxy, and R⁸ ishydrogen atom; a lower alkoxy group; or a lower alkyl group optionallysubstituted with hydroxy or lower alkoxy; provided that when R⁴ is thegroup —CR⁶R⁷R⁸wherein R⁶ is a lower alkyl group optionally substitutedwith halogen, R⁷ is a lower alkyl group optionally substituted withhalogen, and R⁸ is hydrogen atom or a lower alkyl group, or when R⁴ isthe group —CH₂-R⁵ wherein R⁵ is the same as the above, R³ should behydrogen atom, hydroxy group or a cycloalkyl group; and a salt thereof,which comprises (1) reacting a compound of the formula (II):

or its salt, with a compound of (III) H₂N—R⁴ (III) or its salt, whereinR¹, R², R³, R⁴ and A are as defined above, or (2) reacting a compound ofthe formula (IV):

or its salt, with a compound of the formula (V): H₂N—A—R³ (V) or itssalt, wherein R¹, R², R³, R⁴ and A are as defined above, or (3)subjecting a compound of the formula (VI):

or its salt, to reductive alkylation with a compound of formula (VII):

or its salt, wherein R¹, R², R³, R⁶, R⁷ and A are as defined above. 11.A pharmaceutical composition which comprises, as an active ingredient, acompound of claim 1 or a pharmaceutically acceptable salt thereof inadmixture with a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition comprising a compound of claim 1, as anactive ingredient, in association with a pharmaceutically acceptable,substantially non-toxic carrier or excipient.
 13. A composition of claim11 for the use of the treatment and/or prevention of angina,hypertension, pulmonary hypertension, congestive heart failure,glomerular diseases, renal tubulo-intestitinal diseases, renal failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, stroke, bronchitis, asthma, allergic rhinitis,urticaria, glaucoma, diseases characterized by disorders of gutmotility, electile dysfunction, female sexual dysfunction, impotence,diabetic complications, micturition disorder, or incontinence or storageof urine disorder.
 14. A composition of claim 11 for the use of thetreatment of electile dysfunction or impotence.
 15. A use of thecompound of claim 1 for the manufacture of a medicament for inhibitingcGMP-PDE.
 16. A use of the compound of claim 1 for the manufacture of amedicament for treatment and/or prevention of angina, hypertension,pulmonary hypertension, congestive heart failure, glomerular diseases,renal tubulo-intestitinal diseases, renal failure, atherosclerosis,conditions of reduced blood vessel patency, peripheral vascular disease,stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma,diseases characterized by disorders of gut motility, electiledysfunction, female sexual dysfunction, impotence, diabeticcomplications, micturition disorder, or incontinence or storage of urinedisorder.
 17. A method for the treatment and/or prevention of angina,hypertension, pulmonary hypertension, congestive heart failure,glomerular diseases, renal tubulo-intestitinal diseases, renal failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, stroke, bronchitis, asthma, allergic rhinitis,urticaria, glaucoma, diseases characterized by disorders of gutmotility, electile dysfunction, female sexual dysfunction, impotence,diabetic complications, micturition disorder, or incontinence or storageof urine disorder, by administering the compound of claim 1.